Applied Evidence

Judging from our systematic review of the literature, probiotic supplementation is not effective universally for lactose intolerance in adults. However, some evidence suggests that specific strains, concentrations, and preparations of probiotics can be effective.

Discuss probiotic supplementation with lactose-intolerant patients. “Try it” is a reasonable suggestion, given additional evidence that there are individuals whose symptoms of lactose intolerance will, for unknown reasons, respond to probiotics.

For those who find no benefit in probiotics, several other therapeutic options can be recommended.

Prevailing wisdom about lactose intolerance

Lactose intolerant persons suffer such symptoms as abdominal cramping, bloating, and diarrhea after ingesting lactose-containing foods, including nonfermented dairy products.¹ This intolerance to dairy products may result in a person receiving less than the recommended intake of calcium and protein, especially in developing countries.

Primary lactase deficiency is the most common form of lactose intolerance.¹ In the US, 15% of Caucasians, over 50% of Mexican Americans, and over 80% of African Americans have lactose intolerance.²

Treatment options for lactase deficiency

Lactose-intolerant persons digest yogurt, which is fermented, more easily than milk.² Nonfermented lactose-containing foods can be consumed in small quantities or with proteins and fats to delay gastric emptying. Nonfermented dairy products are generally tolerated if they are prehydrolyzed to reduce levels of lactose (such as reduced-lactose or lactose-free milk). Finally, synthetic enzyme (lactase) tablets can be taken with lactose-containing dairy foods in an attempt to alleviate symptoms.²

What are probiotics?

Probiotics are live microorganisms that, when ingested, have beneficial effects on the prevention or treatment of disease.³ Some probiotics, such as Lactobacillus, contain β-galactosidase or lactase intracellularly so that ingestion of lactase-containing probiotics might be beneficial for lactose-intolerant individuals, either consumed with food or taken separately as a supplement.

Theoretically, probiotics ingested as supplements would adhere to the intestinal lining and digest dietary lactose, thereby alleviating malabsorptive symptoms from excessive lactose. Probiotics have other positive effects: treating and preventing diarrhea (infectious and antibiotic induced), relieving symptoms of irritable bowel syndrome, alleviating inflammatory bowel disease, and decreasing atopic disease.^4,5 The Food and Agriculture Organization of the United Nations and the World Health Organization have reported that there is adequate scientific evidence of the potential for probiotic foods to provide health benefits, and that specific strains are safe for human use.⁶

Purported advantages of probiotics. Probiotic supplementation may be preferred over lactose-free products due to the inability to monitor and control all dairy products consumed. The varied efficacy of lactase enzymes in different individuals may render probiotics the favored supplement. Also, the option of a natural treatment may appeal to many people.

Testing for lactose intolerance

The hydrogen breath test is the gold standard for diagnosing lactose intolerance. Intestinal bacteria metabolize carbohydrate to generate hydrogen that is rapidly absorbed into the blood perfusing the gut and cleared during a single passage through the lungs.

A lactose dose of 25 to 50 g is given after an overnight fast. A rise in the hydrogen level of more than 20 parts per million (ppm) over baseline suggests hypolactasia.⁷ At a cutoff of 20 ppm, the test has a specificity of 90%. False positives may occur secondary to severe bacterial overgrowth of the small bowel, smoking, and aspirin use. False negative results are seen in persons receiving oral antibiotics or high colonic enemas, suffering severe diarrhea, or lacking bacterial flora.⁸

Another use of the breath hydrogen test is to measure the quantity of lactose malabsorbed. This theory was based on a study of lactulose in which ingested doses of 5, 10, or 20 g resulted in a linear increase in breath hydrogen along with the similar malabsorption patterns of lactulose and lactose.⁹

The purpose of our systematic review was to determine if probiotics have a positive effect in patients with lactose intolerance. We found no systematic reviews or meta-analyses in the Cochrane Database of Systematic Reviews or the Database of Reviews of Effectiveness (DARE).

Methods

Inclusion criteria

The clinical question researched was “Does the addition of probiotics to nonfermented dairy products decrease lactose intolerance at a single meal?” Inclusion criteria for review were studies that were randomized placebo-controlled clinical trials, that involved adults diagnosed with lactose intolerance via breath hydrogen >20 ppm above baseline after lactose consumption, that used probiotic supplementation in any form as the intervention, and that included the outcomes of symptoms or breath hydrogen test results.

Search strategy and assessment

Four authors (MD, KK, KL, JM) independently searched Medline and Allied and Complementary Medicine Database (AMED) for studies published between 1966 and December 2002. Four authors performed individual searches using the Medical Subject Heading (MeSH) terms 1) “lactose intolerance” and “Lactobacillus”; 2) “lactose intolerance” and “probiotics”; 3) “lactose intolerance” and “yogurt”; and 4) “diarrhea, bloating, abdominal pain” and “yogurt.” The search strategies for each member were documented, and the resulting published listings were combined.

The initial set of articles was pulled and references from those studies were searched. In addition, manufacturers of Lactobacillus supplements and authors identified with expertise in lactose intolerance were contacted by phone or e-mail in an effort to look for any unpublished or ongoing trials possibly missed in the initial search.

Each author independently assessed each of the selected articles for validity using the recommendations made by the Evidence-Based Medicine Working Group at McMaster University.¹⁰ These validity criteria included patient similarity, evidence of controls, randomization, allocation concealment, blinding, completion of follow-up, use of intention-to-treat, and similarity of intervention and control groups. The authors then met to discuss their assessment and clarify any article concerns. General agreement was reached, and there were no dissenting views.

Data extraction

A standardized data extraction form was developed by 1 author (FD) and each paper’s information was extracted by 1 of the other authors (KL) and verified by the final author (FD). The following data were extracted: number of treatment arms, types of treatment arms (including forms of probiotics), number of subjects per treatment arm, study design, data presentation, and results obtained.

No formal statistical procedures or tests were performed. Authors hoped that appropriate data could be collected from each paper so that a meta-analysis could be performed. However, the lack of standardized data presentation for breath hydrogen and symptom results made data pooling impossible.

Results

Medline and AMED searches yielded 75 clinical trials. The reference search from these studies gave an additional 15 trials. No studies were identified through manufacturer or expert author inquiries. From the master list of 90 studies, 22 met inclusion and exclusion criteria. Of the 22, 10 were consistent with our clinical question. Of these 10 articles used in the study, 8 were obtained from the Medline and AMED searches, and 2 were obtained from the references.

Of the 10 randomized placebo-controlled trials, sample sizes for probiotic treatment arms ranged from 5 (Dehkordi) to 20 (Lin & Yen). Probiotic arms varied in subtype, strain, and concentration. Most of the studies (9) used the Lactobacillus acidophilus subtype as the intervention. Four trials examined probiotics other than, or in addition to, L acidophilus (Dehkordi, Jiang, Lin & Yen, Lin & Savaiano). Dehkordi performed 2 experiments. The first experiment examined the additive of effect of Lactobacillus and Bifidobacterium longum. The second compared only Lactobacillus strains with control milk.

Lin & Savaiano in 1990 compared 3 Lactobacillus strains, each with 2 different concentrations, as well as the combination probiotic subtypes of Streptococcus thermophilus/Lactobacillus bulgaricus at 2 concentrations with the control milk.

In 1998, Lin & Yen compared 2 concentrations of an L acidophilus strain and 2 concentrations of an L bulgaricus strain with placebo. McDonough examined the effects of sonicated (intracellular lactase release) acidophilus milk in addition to acidophilus milk on breath hydrogen results.

Four of the 10 randomized controlled trials were performed in a crossover design (Newcomer, Lin & Savaiano, Lin & Yen, and Savaiano) while the remaining 6 varied in randomized designs.

TABLE 1 shows the validity characteristics for the 10 clinical trials published between 1981 and 1998 that met inclusion and exclusion criteria. While all were randomized controlled trials with similar patients, interventions, and controls, none of the 10 concealed the allocation of the interventions. Lin & Yen’s 1998 study failed to mention the percentage of subjects followed-up and, thus, intention-to-treat did not figure into the analysis. Three of the 10 (Dehkordi, Onwulata, McDonough) did not specify if their studies involved double-blinding.

Descriptors of each trial’s treatment arms, subjects, design, data presentation, and results are shown in TABLE W1. Of the 9 studies that measured the disease-oriented outcome of breath hydrogen, 3 were positive, 3 were negative, and 3 had both positive and negative (mixed) results. Of the 7 studies that measured the patient-oriented outcome of symptoms, 1 yielded positive results, 5 were negative, and 1 had mixed outcomes (TABLE 2).

TABLE 1
Validity characteristics of randomized controlled trials studying the effects of probiotics on lactose intolerance

TABLE 2
Does the addition of probiotics to non-fermented dairy products decrease lactose intolerance at a single meal?

Discussion

This review of controlled clinical trials produced a negative answer to the question: “Do probiotics decrease lactose intolerance at a single meal including nonfermented dairy products?” We reviewed articles that involved the simultaneous combination of probiotics and non-fermented dairy products in objectively identified lactose-intolerant individuals.

Strengths of this review

All review studies selected patients who had both gastrointestinal symptoms and positive breath hydrogen test results. All studies used appropriate methodology of randomized design (LOE: 1b). All studies involved a control group or a crossover design in which intervention patients served as their own controls. Further strengths of this review are an adequate number of studies with strong methodology, most (7 of 10) measured the patient-oriented outcome of symptoms, and reports of no adverse effects of probiotic treatments.

Weaknesses of the review

The variations in probiotic subtype, strain, and concentration are weaknesses in this review. Probiotic subtypes and strains vary with regard to β-galactosidase activity, intestinal adherence, cell wall thickness, and other characteristics that may affect clinical efficacy. Jiang showed significant breath hydrogen results with B longum B6 grown in lactose-containing media, while the same strain grown in glucose- and lactose-containing media was not effective. He also found the former strain significantly reduced the symptom of flatulence but not pain, meteorism, borborygmi, or diarrhea.

Only 2 of the 9 L acidophilus studies reported use of similar strains of L acidophilus B (Mustapha, Lin and Yen). Six of the 9 L acidophilus studies accounted for the probiotic subtype and concentration but not its strain. Instead the L acidophilus intervention was expressed as L acidophilus milk or sweet acidophilus milk (Dehkordi, Newcomer, Onwulata, Savaiano, McDonough, Kim). A potential strain outcome association may exist with L acidophilus B. Both Mustapha and Lin and Yen showed positive outcomes with this treatment arm in breath hydrogen and symptom results (TABLE W1).

Trials using L bulgaricus (Lin, Savaiano, and Lin and Yen) may have isolated a therapeutic subtype other than acidophilus. Lin, Savaiano found that 1 of 2 L bulgaricus/S thermophilus combinations significantly reduced symptoms. Whether this difference may be attributed to 1 of the 2 subtypes or their combination can only be speculated.

Additionally, Lin and Yen found that both strains of L bulgaricus 449 at concentrations of 10⁸ and 10⁹ significantly improved breath hydrogen and symptom scores. This positive association may be related to any or all of its subtype, strain, or concentration. Also in that study, both probiotic subtypes of L acidophilus and L bulgaricus at concentrations of 10⁹ significantly reduce symptoms. Unfortunately, there was not enough specific information on strain characteristics to draw any firm conclusions. In future studies, careful attention to bacterial characteristics may provide a definitive answer to our questions.

The lack of standardized data presentation for breath hydrogen and symptoms in these 10 trials was a limitation. Some papers had only graphs of mean breath hydrogen, some showed differences from baseline, and some showed various summary statistics of breath hydrogen over different time periods. There was no standard objective measure of symptoms such as a Likert scale. Instead, symptoms were expressed in various ways (number of instances, scoring systems, or sole mention in text format). For these reasons, a meta-analysis could not be performed. This review could be further criticized because authors were not directly contacted for raw data for a potential meta-analysis.

Recommendations from this review

Several recommendations can be extracted from the results of this review.

First, probiotics in general do not reduce lactose intolerance (SOR: A). However, some evidence suggests that specific strains and concentrations are effective (SOR: B).

Second, there were enough positive treatment arms to suggest that some individuals will, for unknown reasons, have their symptoms eliminated or reduced with probiotics (SOR: B). It is reasonable, therefore, for clinicians to simply tell patients to “try it.” For a more objective analysis, an n-of-1 trial could be used.²¹ Clinicians will have to keep in mind that many people presumed to have lactose intolerance do not meet standard diagnostic criteria when objectively assessed.

Third, several strategies are available to lactose-intolerant persons (SOR: C). Yogurt, lactase enzymes, lactose-free or lactose-reduced products, specific foods, and probiotics selective for strain, concentration, and preparation are all supported by evidence. Onwulata compared results of probiotic milk, lactase tablets plus milk, hydrolyzed lactose milk, and yogurt with that of whole milk. Only yogurt and hydrolyzed lactose milk yielded significantly lower breath hydrogen results. Six of 10 patients reported symptoms with probiotic milk, 3 of 10 with lactase tablets, 1 of 10 with hydrolyzed milk, and no symptoms were reported with yogurt.

Dehkordi showed that probiotic milk had no effect on breath hydrogen results, but his treatment arm of cornflakes with whole milk did significantly affect results. McDonough found that when sweet acidophilus milk was sonicated to release intracellular lactase from the bacterial cells, a significant change in breath hydrogen resulted. Unfortunately, neither Dehkordi nor McDonough measured symptoms in their studies to specify patient-oriented outcomes.

Fourth, many individuals with symptoms of lactose intolerance do not meet the definition of diagnosis as measured by breath hydrogen testing (SOR: B). All clinical trials in this review declined subject enrollment if lactose intolerance symptoms were unconfirmed by breath hydrogen testing, thereby accepting only true positives.

There are several reasons why probiotic supplementation may be superior to commercial lactase supplementation. Patients have varied responses to lactase supplementation with meals, and different preparations may be more or less effective for the same quantity of lactose ingested.²² Also, as mentioned earlier, other research supports the role of probiotics in preventing diarrheal illness, treating irritable bowel syndrome and inflammatory bowel disease, and possibly benefiting persons with atopic disease. Finally, if lactase-producing probiotics are clinically effective and can also adhere to the intestinal lining, patients may experience prolonged reduction or remission of symptoms without the need to ingest any tablets with meals.

Two of the 10 studies (Newcomer, Kim) examined long-term probiotic use for 1 and 2 weeks, respectively. Newcomer measured only symptoms, showing no significant difference between L acidophilus milk and unaltered milk. Kim found that 2 of 3 L acidophilus concentrations significantly decreased breath hydrogen results, but the study did not measure symptoms. We can infer a negative patient-oriented outcome of long-term probiotic intervention based on these 2 trials. However, this domain of chronic probiotic use to reduce lactose intolerance would benefit from additional studies for comparison.

In conclusion, probiotic supplementation in general was not effective at reducing lactose intolerance of adults. Some evidence suggests that certain strains, concentrations, and preparations are effective. Clinicians could discuss probiotic supplementation with patients as an alternative treatment. There were enough positive treatment arms to suggest there may be individuals who respond to probiotics. Further studies are needed to determine specific probiotic relationships. The best studies would be those using crossover randomized double-blind design of selected probiotic strains and concentrations and objectively measuring breath hydrogen and symptoms with a long enough wash-out period to eliminate the chance of gut colonization.

Acknowledgments

Material in this article has been previously presented at the following: “Probiotic Supplementation as Treatment for Lactose Intolerance: a Systematic Review,” Fellows works-in-progress poster presentation at the STFM 36th Annual Conference, Atlanta, GA, September 2003, Kara M. Levri, Kari Ketvertis, Mark Deramo, Joel H. Merenstein, Frank D’Amico; “Probiotic Supplementation as Treatment for Lactose Intolerance: A Systematic Review,” Grand Professor Rounds, UPMC St. Margaret, Pittsburgh, Pa, June 2003, Kara M. Levri, Kari Ketvertis, Mark Deramo; “Probiotic Supplementation as Treatment for Lactose Intolerance: a Systematic Review,” Pennsylvania Academy of Family Physicians Research Day, Philadelphia, Pa, April 2003, Kara M. Levri.

CORRESPONDING AUTHOR
Kara M. Levri, MD, MPH, UPMC St. Margaret, 3937 Butler Street, Pittsburgh, PA 15201. E-mail: [email protected].

Judging from our systematic review of the literature, probiotic supplementation is not effective universally for lactose intolerance in adults. However, some evidence suggests that specific strains, concentrations, and preparations of probiotics can be effective.

Discuss probiotic supplementation with lactose-intolerant patients. “Try it” is a reasonable suggestion, given additional evidence that there are individuals whose symptoms of lactose intolerance will, for unknown reasons, respond to probiotics.

For those who find no benefit in probiotics, several other therapeutic options can be recommended.

Prevailing wisdom about lactose intolerance

Lactose intolerant persons suffer such symptoms as abdominal cramping, bloating, and diarrhea after ingesting lactose-containing foods, including nonfermented dairy products.¹ This intolerance to dairy products may result in a person receiving less than the recommended intake of calcium and protein, especially in developing countries.

Primary lactase deficiency is the most common form of lactose intolerance.¹ In the US, 15% of Caucasians, over 50% of Mexican Americans, and over 80% of African Americans have lactose intolerance.²

Treatment options for lactase deficiency

Lactose-intolerant persons digest yogurt, which is fermented, more easily than milk.² Nonfermented lactose-containing foods can be consumed in small quantities or with proteins and fats to delay gastric emptying. Nonfermented dairy products are generally tolerated if they are prehydrolyzed to reduce levels of lactose (such as reduced-lactose or lactose-free milk). Finally, synthetic enzyme (lactase) tablets can be taken with lactose-containing dairy foods in an attempt to alleviate symptoms.²

What are probiotics?

Probiotics are live microorganisms that, when ingested, have beneficial effects on the prevention or treatment of disease.³ Some probiotics, such as Lactobacillus, contain β-galactosidase or lactase intracellularly so that ingestion of lactase-containing probiotics might be beneficial for lactose-intolerant individuals, either consumed with food or taken separately as a supplement.

Theoretically, probiotics ingested as supplements would adhere to the intestinal lining and digest dietary lactose, thereby alleviating malabsorptive symptoms from excessive lactose. Probiotics have other positive effects: treating and preventing diarrhea (infectious and antibiotic induced), relieving symptoms of irritable bowel syndrome, alleviating inflammatory bowel disease, and decreasing atopic disease.^4,5 The Food and Agriculture Organization of the United Nations and the World Health Organization have reported that there is adequate scientific evidence of the potential for probiotic foods to provide health benefits, and that specific strains are safe for human use.⁶

Purported advantages of probiotics. Probiotic supplementation may be preferred over lactose-free products due to the inability to monitor and control all dairy products consumed. The varied efficacy of lactase enzymes in different individuals may render probiotics the favored supplement. Also, the option of a natural treatment may appeal to many people.

Testing for lactose intolerance

The hydrogen breath test is the gold standard for diagnosing lactose intolerance. Intestinal bacteria metabolize carbohydrate to generate hydrogen that is rapidly absorbed into the blood perfusing the gut and cleared during a single passage through the lungs.

A lactose dose of 25 to 50 g is given after an overnight fast. A rise in the hydrogen level of more than 20 parts per million (ppm) over baseline suggests hypolactasia.⁷ At a cutoff of 20 ppm, the test has a specificity of 90%. False positives may occur secondary to severe bacterial overgrowth of the small bowel, smoking, and aspirin use. False negative results are seen in persons receiving oral antibiotics or high colonic enemas, suffering severe diarrhea, or lacking bacterial flora.⁸

Another use of the breath hydrogen test is to measure the quantity of lactose malabsorbed. This theory was based on a study of lactulose in which ingested doses of 5, 10, or 20 g resulted in a linear increase in breath hydrogen along with the similar malabsorption patterns of lactulose and lactose.⁹

The purpose of our systematic review was to determine if probiotics have a positive effect in patients with lactose intolerance. We found no systematic reviews or meta-analyses in the Cochrane Database of Systematic Reviews or the Database of Reviews of Effectiveness (DARE).

Methods

Inclusion criteria

The clinical question researched was “Does the addition of probiotics to nonfermented dairy products decrease lactose intolerance at a single meal?” Inclusion criteria for review were studies that were randomized placebo-controlled clinical trials, that involved adults diagnosed with lactose intolerance via breath hydrogen >20 ppm above baseline after lactose consumption, that used probiotic supplementation in any form as the intervention, and that included the outcomes of symptoms or breath hydrogen test results.

Search strategy and assessment

Four authors (MD, KK, KL, JM) independently searched Medline and Allied and Complementary Medicine Database (AMED) for studies published between 1966 and December 2002. Four authors performed individual searches using the Medical Subject Heading (MeSH) terms 1) “lactose intolerance” and “Lactobacillus”; 2) “lactose intolerance” and “probiotics”; 3) “lactose intolerance” and “yogurt”; and 4) “diarrhea, bloating, abdominal pain” and “yogurt.” The search strategies for each member were documented, and the resulting published listings were combined.

The initial set of articles was pulled and references from those studies were searched. In addition, manufacturers of Lactobacillus supplements and authors identified with expertise in lactose intolerance were contacted by phone or e-mail in an effort to look for any unpublished or ongoing trials possibly missed in the initial search.

Each author independently assessed each of the selected articles for validity using the recommendations made by the Evidence-Based Medicine Working Group at McMaster University.¹⁰ These validity criteria included patient similarity, evidence of controls, randomization, allocation concealment, blinding, completion of follow-up, use of intention-to-treat, and similarity of intervention and control groups. The authors then met to discuss their assessment and clarify any article concerns. General agreement was reached, and there were no dissenting views.

Data extraction

A standardized data extraction form was developed by 1 author (FD) and each paper’s information was extracted by 1 of the other authors (KL) and verified by the final author (FD). The following data were extracted: number of treatment arms, types of treatment arms (including forms of probiotics), number of subjects per treatment arm, study design, data presentation, and results obtained.

No formal statistical procedures or tests were performed. Authors hoped that appropriate data could be collected from each paper so that a meta-analysis could be performed. However, the lack of standardized data presentation for breath hydrogen and symptom results made data pooling impossible.

Results

Medline and AMED searches yielded 75 clinical trials. The reference search from these studies gave an additional 15 trials. No studies were identified through manufacturer or expert author inquiries. From the master list of 90 studies, 22 met inclusion and exclusion criteria. Of the 22, 10 were consistent with our clinical question. Of these 10 articles used in the study, 8 were obtained from the Medline and AMED searches, and 2 were obtained from the references.

Of the 10 randomized placebo-controlled trials, sample sizes for probiotic treatment arms ranged from 5 (Dehkordi) to 20 (Lin & Yen). Probiotic arms varied in subtype, strain, and concentration. Most of the studies (9) used the Lactobacillus acidophilus subtype as the intervention. Four trials examined probiotics other than, or in addition to, L acidophilus (Dehkordi, Jiang, Lin & Yen, Lin & Savaiano). Dehkordi performed 2 experiments. The first experiment examined the additive of effect of Lactobacillus and Bifidobacterium longum. The second compared only Lactobacillus strains with control milk.

Lin & Savaiano in 1990 compared 3 Lactobacillus strains, each with 2 different concentrations, as well as the combination probiotic subtypes of Streptococcus thermophilus/Lactobacillus bulgaricus at 2 concentrations with the control milk.

In 1998, Lin & Yen compared 2 concentrations of an L acidophilus strain and 2 concentrations of an L bulgaricus strain with placebo. McDonough examined the effects of sonicated (intracellular lactase release) acidophilus milk in addition to acidophilus milk on breath hydrogen results.

Four of the 10 randomized controlled trials were performed in a crossover design (Newcomer, Lin & Savaiano, Lin & Yen, and Savaiano) while the remaining 6 varied in randomized designs.

TABLE 1 shows the validity characteristics for the 10 clinical trials published between 1981 and 1998 that met inclusion and exclusion criteria. While all were randomized controlled trials with similar patients, interventions, and controls, none of the 10 concealed the allocation of the interventions. Lin & Yen’s 1998 study failed to mention the percentage of subjects followed-up and, thus, intention-to-treat did not figure into the analysis. Three of the 10 (Dehkordi, Onwulata, McDonough) did not specify if their studies involved double-blinding.

Descriptors of each trial’s treatment arms, subjects, design, data presentation, and results are shown in TABLE W1. Of the 9 studies that measured the disease-oriented outcome of breath hydrogen, 3 were positive, 3 were negative, and 3 had both positive and negative (mixed) results. Of the 7 studies that measured the patient-oriented outcome of symptoms, 1 yielded positive results, 5 were negative, and 1 had mixed outcomes (TABLE 2).

TABLE 1
Validity characteristics of randomized controlled trials studying the effects of probiotics on lactose intolerance

TABLE 2
Does the addition of probiotics to non-fermented dairy products decrease lactose intolerance at a single meal?

Discussion

This review of controlled clinical trials produced a negative answer to the question: “Do probiotics decrease lactose intolerance at a single meal including nonfermented dairy products?” We reviewed articles that involved the simultaneous combination of probiotics and non-fermented dairy products in objectively identified lactose-intolerant individuals.

Strengths of this review

All review studies selected patients who had both gastrointestinal symptoms and positive breath hydrogen test results. All studies used appropriate methodology of randomized design (LOE: 1b). All studies involved a control group or a crossover design in which intervention patients served as their own controls. Further strengths of this review are an adequate number of studies with strong methodology, most (7 of 10) measured the patient-oriented outcome of symptoms, and reports of no adverse effects of probiotic treatments.

Weaknesses of the review

The variations in probiotic subtype, strain, and concentration are weaknesses in this review. Probiotic subtypes and strains vary with regard to β-galactosidase activity, intestinal adherence, cell wall thickness, and other characteristics that may affect clinical efficacy. Jiang showed significant breath hydrogen results with B longum B6 grown in lactose-containing media, while the same strain grown in glucose- and lactose-containing media was not effective. He also found the former strain significantly reduced the symptom of flatulence but not pain, meteorism, borborygmi, or diarrhea.

Only 2 of the 9 L acidophilus studies reported use of similar strains of L acidophilus B (Mustapha, Lin and Yen). Six of the 9 L acidophilus studies accounted for the probiotic subtype and concentration but not its strain. Instead the L acidophilus intervention was expressed as L acidophilus milk or sweet acidophilus milk (Dehkordi, Newcomer, Onwulata, Savaiano, McDonough, Kim). A potential strain outcome association may exist with L acidophilus B. Both Mustapha and Lin and Yen showed positive outcomes with this treatment arm in breath hydrogen and symptom results (TABLE W1).

Trials using L bulgaricus (Lin, Savaiano, and Lin and Yen) may have isolated a therapeutic subtype other than acidophilus. Lin, Savaiano found that 1 of 2 L bulgaricus/S thermophilus combinations significantly reduced symptoms. Whether this difference may be attributed to 1 of the 2 subtypes or their combination can only be speculated.

Additionally, Lin and Yen found that both strains of L bulgaricus 449 at concentrations of 10⁸ and 10⁹ significantly improved breath hydrogen and symptom scores. This positive association may be related to any or all of its subtype, strain, or concentration. Also in that study, both probiotic subtypes of L acidophilus and L bulgaricus at concentrations of 10⁹ significantly reduce symptoms. Unfortunately, there was not enough specific information on strain characteristics to draw any firm conclusions. In future studies, careful attention to bacterial characteristics may provide a definitive answer to our questions.

The lack of standardized data presentation for breath hydrogen and symptoms in these 10 trials was a limitation. Some papers had only graphs of mean breath hydrogen, some showed differences from baseline, and some showed various summary statistics of breath hydrogen over different time periods. There was no standard objective measure of symptoms such as a Likert scale. Instead, symptoms were expressed in various ways (number of instances, scoring systems, or sole mention in text format). For these reasons, a meta-analysis could not be performed. This review could be further criticized because authors were not directly contacted for raw data for a potential meta-analysis.

Recommendations from this review

Several recommendations can be extracted from the results of this review.

First, probiotics in general do not reduce lactose intolerance (SOR: A). However, some evidence suggests that specific strains and concentrations are effective (SOR: B).

Second, there were enough positive treatment arms to suggest that some individuals will, for unknown reasons, have their symptoms eliminated or reduced with probiotics (SOR: B). It is reasonable, therefore, for clinicians to simply tell patients to “try it.” For a more objective analysis, an n-of-1 trial could be used.²¹ Clinicians will have to keep in mind that many people presumed to have lactose intolerance do not meet standard diagnostic criteria when objectively assessed.

Third, several strategies are available to lactose-intolerant persons (SOR: C). Yogurt, lactase enzymes, lactose-free or lactose-reduced products, specific foods, and probiotics selective for strain, concentration, and preparation are all supported by evidence. Onwulata compared results of probiotic milk, lactase tablets plus milk, hydrolyzed lactose milk, and yogurt with that of whole milk. Only yogurt and hydrolyzed lactose milk yielded significantly lower breath hydrogen results. Six of 10 patients reported symptoms with probiotic milk, 3 of 10 with lactase tablets, 1 of 10 with hydrolyzed milk, and no symptoms were reported with yogurt.

Dehkordi showed that probiotic milk had no effect on breath hydrogen results, but his treatment arm of cornflakes with whole milk did significantly affect results. McDonough found that when sweet acidophilus milk was sonicated to release intracellular lactase from the bacterial cells, a significant change in breath hydrogen resulted. Unfortunately, neither Dehkordi nor McDonough measured symptoms in their studies to specify patient-oriented outcomes.

Fourth, many individuals with symptoms of lactose intolerance do not meet the definition of diagnosis as measured by breath hydrogen testing (SOR: B). All clinical trials in this review declined subject enrollment if lactose intolerance symptoms were unconfirmed by breath hydrogen testing, thereby accepting only true positives.

There are several reasons why probiotic supplementation may be superior to commercial lactase supplementation. Patients have varied responses to lactase supplementation with meals, and different preparations may be more or less effective for the same quantity of lactose ingested.²² Also, as mentioned earlier, other research supports the role of probiotics in preventing diarrheal illness, treating irritable bowel syndrome and inflammatory bowel disease, and possibly benefiting persons with atopic disease. Finally, if lactase-producing probiotics are clinically effective and can also adhere to the intestinal lining, patients may experience prolonged reduction or remission of symptoms without the need to ingest any tablets with meals.

Two of the 10 studies (Newcomer, Kim) examined long-term probiotic use for 1 and 2 weeks, respectively. Newcomer measured only symptoms, showing no significant difference between L acidophilus milk and unaltered milk. Kim found that 2 of 3 L acidophilus concentrations significantly decreased breath hydrogen results, but the study did not measure symptoms. We can infer a negative patient-oriented outcome of long-term probiotic intervention based on these 2 trials. However, this domain of chronic probiotic use to reduce lactose intolerance would benefit from additional studies for comparison.

In conclusion, probiotic supplementation in general was not effective at reducing lactose intolerance of adults. Some evidence suggests that certain strains, concentrations, and preparations are effective. Clinicians could discuss probiotic supplementation with patients as an alternative treatment. There were enough positive treatment arms to suggest there may be individuals who respond to probiotics. Further studies are needed to determine specific probiotic relationships. The best studies would be those using crossover randomized double-blind design of selected probiotic strains and concentrations and objectively measuring breath hydrogen and symptoms with a long enough wash-out period to eliminate the chance of gut colonization.

Acknowledgments

Material in this article has been previously presented at the following: “Probiotic Supplementation as Treatment for Lactose Intolerance: a Systematic Review,” Fellows works-in-progress poster presentation at the STFM 36th Annual Conference, Atlanta, GA, September 2003, Kara M. Levri, Kari Ketvertis, Mark Deramo, Joel H. Merenstein, Frank D’Amico; “Probiotic Supplementation as Treatment for Lactose Intolerance: A Systematic Review,” Grand Professor Rounds, UPMC St. Margaret, Pittsburgh, Pa, June 2003, Kara M. Levri, Kari Ketvertis, Mark Deramo; “Probiotic Supplementation as Treatment for Lactose Intolerance: a Systematic Review,” Pennsylvania Academy of Family Physicians Research Day, Philadelphia, Pa, April 2003, Kara M. Levri.

CORRESPONDING AUTHOR
Kara M. Levri, MD, MPH, UPMC St. Margaret, 3937 Butler Street, Pittsburgh, PA 15201. E-mail: [email protected].

Judging from our systematic review of the literature, probiotic supplementation is not effective universally for lactose intolerance in adults. However, some evidence suggests that specific strains, concentrations, and preparations of probiotics can be effective.

Discuss probiotic supplementation with lactose-intolerant patients. “Try it” is a reasonable suggestion, given additional evidence that there are individuals whose symptoms of lactose intolerance will, for unknown reasons, respond to probiotics.

For those who find no benefit in probiotics, several other therapeutic options can be recommended.

Prevailing wisdom about lactose intolerance

Lactose intolerant persons suffer such symptoms as abdominal cramping, bloating, and diarrhea after ingesting lactose-containing foods, including nonfermented dairy products.¹ This intolerance to dairy products may result in a person receiving less than the recommended intake of calcium and protein, especially in developing countries.

Primary lactase deficiency is the most common form of lactose intolerance.¹ In the US, 15% of Caucasians, over 50% of Mexican Americans, and over 80% of African Americans have lactose intolerance.²

Treatment options for lactase deficiency

Lactose-intolerant persons digest yogurt, which is fermented, more easily than milk.² Nonfermented lactose-containing foods can be consumed in small quantities or with proteins and fats to delay gastric emptying. Nonfermented dairy products are generally tolerated if they are prehydrolyzed to reduce levels of lactose (such as reduced-lactose or lactose-free milk). Finally, synthetic enzyme (lactase) tablets can be taken with lactose-containing dairy foods in an attempt to alleviate symptoms.²

What are probiotics?

Probiotics are live microorganisms that, when ingested, have beneficial effects on the prevention or treatment of disease.³ Some probiotics, such as Lactobacillus, contain β-galactosidase or lactase intracellularly so that ingestion of lactase-containing probiotics might be beneficial for lactose-intolerant individuals, either consumed with food or taken separately as a supplement.

Theoretically, probiotics ingested as supplements would adhere to the intestinal lining and digest dietary lactose, thereby alleviating malabsorptive symptoms from excessive lactose. Probiotics have other positive effects: treating and preventing diarrhea (infectious and antibiotic induced), relieving symptoms of irritable bowel syndrome, alleviating inflammatory bowel disease, and decreasing atopic disease.^4,5 The Food and Agriculture Organization of the United Nations and the World Health Organization have reported that there is adequate scientific evidence of the potential for probiotic foods to provide health benefits, and that specific strains are safe for human use.⁶

Purported advantages of probiotics. Probiotic supplementation may be preferred over lactose-free products due to the inability to monitor and control all dairy products consumed. The varied efficacy of lactase enzymes in different individuals may render probiotics the favored supplement. Also, the option of a natural treatment may appeal to many people.

Testing for lactose intolerance

The hydrogen breath test is the gold standard for diagnosing lactose intolerance. Intestinal bacteria metabolize carbohydrate to generate hydrogen that is rapidly absorbed into the blood perfusing the gut and cleared during a single passage through the lungs.

A lactose dose of 25 to 50 g is given after an overnight fast. A rise in the hydrogen level of more than 20 parts per million (ppm) over baseline suggests hypolactasia.⁷ At a cutoff of 20 ppm, the test has a specificity of 90%. False positives may occur secondary to severe bacterial overgrowth of the small bowel, smoking, and aspirin use. False negative results are seen in persons receiving oral antibiotics or high colonic enemas, suffering severe diarrhea, or lacking bacterial flora.⁸

Another use of the breath hydrogen test is to measure the quantity of lactose malabsorbed. This theory was based on a study of lactulose in which ingested doses of 5, 10, or 20 g resulted in a linear increase in breath hydrogen along with the similar malabsorption patterns of lactulose and lactose.⁹

The purpose of our systematic review was to determine if probiotics have a positive effect in patients with lactose intolerance. We found no systematic reviews or meta-analyses in the Cochrane Database of Systematic Reviews or the Database of Reviews of Effectiveness (DARE).

Methods

Inclusion criteria

The clinical question researched was “Does the addition of probiotics to nonfermented dairy products decrease lactose intolerance at a single meal?” Inclusion criteria for review were studies that were randomized placebo-controlled clinical trials, that involved adults diagnosed with lactose intolerance via breath hydrogen >20 ppm above baseline after lactose consumption, that used probiotic supplementation in any form as the intervention, and that included the outcomes of symptoms or breath hydrogen test results.

Search strategy and assessment

Four authors (MD, KK, KL, JM) independently searched Medline and Allied and Complementary Medicine Database (AMED) for studies published between 1966 and December 2002. Four authors performed individual searches using the Medical Subject Heading (MeSH) terms 1) “lactose intolerance” and “Lactobacillus”; 2) “lactose intolerance” and “probiotics”; 3) “lactose intolerance” and “yogurt”; and 4) “diarrhea, bloating, abdominal pain” and “yogurt.” The search strategies for each member were documented, and the resulting published listings were combined.

The initial set of articles was pulled and references from those studies were searched. In addition, manufacturers of Lactobacillus supplements and authors identified with expertise in lactose intolerance were contacted by phone or e-mail in an effort to look for any unpublished or ongoing trials possibly missed in the initial search.

Each author independently assessed each of the selected articles for validity using the recommendations made by the Evidence-Based Medicine Working Group at McMaster University.¹⁰ These validity criteria included patient similarity, evidence of controls, randomization, allocation concealment, blinding, completion of follow-up, use of intention-to-treat, and similarity of intervention and control groups. The authors then met to discuss their assessment and clarify any article concerns. General agreement was reached, and there were no dissenting views.

Data extraction

A standardized data extraction form was developed by 1 author (FD) and each paper’s information was extracted by 1 of the other authors (KL) and verified by the final author (FD). The following data were extracted: number of treatment arms, types of treatment arms (including forms of probiotics), number of subjects per treatment arm, study design, data presentation, and results obtained.

No formal statistical procedures or tests were performed. Authors hoped that appropriate data could be collected from each paper so that a meta-analysis could be performed. However, the lack of standardized data presentation for breath hydrogen and symptom results made data pooling impossible.

Results

Medline and AMED searches yielded 75 clinical trials. The reference search from these studies gave an additional 15 trials. No studies were identified through manufacturer or expert author inquiries. From the master list of 90 studies, 22 met inclusion and exclusion criteria. Of the 22, 10 were consistent with our clinical question. Of these 10 articles used in the study, 8 were obtained from the Medline and AMED searches, and 2 were obtained from the references.

Of the 10 randomized placebo-controlled trials, sample sizes for probiotic treatment arms ranged from 5 (Dehkordi) to 20 (Lin & Yen). Probiotic arms varied in subtype, strain, and concentration. Most of the studies (9) used the Lactobacillus acidophilus subtype as the intervention. Four trials examined probiotics other than, or in addition to, L acidophilus (Dehkordi, Jiang, Lin & Yen, Lin & Savaiano). Dehkordi performed 2 experiments. The first experiment examined the additive of effect of Lactobacillus and Bifidobacterium longum. The second compared only Lactobacillus strains with control milk.

Lin & Savaiano in 1990 compared 3 Lactobacillus strains, each with 2 different concentrations, as well as the combination probiotic subtypes of Streptococcus thermophilus/Lactobacillus bulgaricus at 2 concentrations with the control milk.

In 1998, Lin & Yen compared 2 concentrations of an L acidophilus strain and 2 concentrations of an L bulgaricus strain with placebo. McDonough examined the effects of sonicated (intracellular lactase release) acidophilus milk in addition to acidophilus milk on breath hydrogen results.

Four of the 10 randomized controlled trials were performed in a crossover design (Newcomer, Lin & Savaiano, Lin & Yen, and Savaiano) while the remaining 6 varied in randomized designs.

TABLE 1 shows the validity characteristics for the 10 clinical trials published between 1981 and 1998 that met inclusion and exclusion criteria. While all were randomized controlled trials with similar patients, interventions, and controls, none of the 10 concealed the allocation of the interventions. Lin & Yen’s 1998 study failed to mention the percentage of subjects followed-up and, thus, intention-to-treat did not figure into the analysis. Three of the 10 (Dehkordi, Onwulata, McDonough) did not specify if their studies involved double-blinding.

Descriptors of each trial’s treatment arms, subjects, design, data presentation, and results are shown in TABLE W1. Of the 9 studies that measured the disease-oriented outcome of breath hydrogen, 3 were positive, 3 were negative, and 3 had both positive and negative (mixed) results. Of the 7 studies that measured the patient-oriented outcome of symptoms, 1 yielded positive results, 5 were negative, and 1 had mixed outcomes (TABLE 2).

TABLE 1
Validity characteristics of randomized controlled trials studying the effects of probiotics on lactose intolerance

TABLE 2
Does the addition of probiotics to non-fermented dairy products decrease lactose intolerance at a single meal?

Discussion

This review of controlled clinical trials produced a negative answer to the question: “Do probiotics decrease lactose intolerance at a single meal including nonfermented dairy products?” We reviewed articles that involved the simultaneous combination of probiotics and non-fermented dairy products in objectively identified lactose-intolerant individuals.

Strengths of this review

All review studies selected patients who had both gastrointestinal symptoms and positive breath hydrogen test results. All studies used appropriate methodology of randomized design (LOE: 1b). All studies involved a control group or a crossover design in which intervention patients served as their own controls. Further strengths of this review are an adequate number of studies with strong methodology, most (7 of 10) measured the patient-oriented outcome of symptoms, and reports of no adverse effects of probiotic treatments.

Weaknesses of the review

The variations in probiotic subtype, strain, and concentration are weaknesses in this review. Probiotic subtypes and strains vary with regard to β-galactosidase activity, intestinal adherence, cell wall thickness, and other characteristics that may affect clinical efficacy. Jiang showed significant breath hydrogen results with B longum B6 grown in lactose-containing media, while the same strain grown in glucose- and lactose-containing media was not effective. He also found the former strain significantly reduced the symptom of flatulence but not pain, meteorism, borborygmi, or diarrhea.

Only 2 of the 9 L acidophilus studies reported use of similar strains of L acidophilus B (Mustapha, Lin and Yen). Six of the 9 L acidophilus studies accounted for the probiotic subtype and concentration but not its strain. Instead the L acidophilus intervention was expressed as L acidophilus milk or sweet acidophilus milk (Dehkordi, Newcomer, Onwulata, Savaiano, McDonough, Kim). A potential strain outcome association may exist with L acidophilus B. Both Mustapha and Lin and Yen showed positive outcomes with this treatment arm in breath hydrogen and symptom results (TABLE W1).

Trials using L bulgaricus (Lin, Savaiano, and Lin and Yen) may have isolated a therapeutic subtype other than acidophilus. Lin, Savaiano found that 1 of 2 L bulgaricus/S thermophilus combinations significantly reduced symptoms. Whether this difference may be attributed to 1 of the 2 subtypes or their combination can only be speculated.

Additionally, Lin and Yen found that both strains of L bulgaricus 449 at concentrations of 10⁸ and 10⁹ significantly improved breath hydrogen and symptom scores. This positive association may be related to any or all of its subtype, strain, or concentration. Also in that study, both probiotic subtypes of L acidophilus and L bulgaricus at concentrations of 10⁹ significantly reduce symptoms. Unfortunately, there was not enough specific information on strain characteristics to draw any firm conclusions. In future studies, careful attention to bacterial characteristics may provide a definitive answer to our questions.

The lack of standardized data presentation for breath hydrogen and symptoms in these 10 trials was a limitation. Some papers had only graphs of mean breath hydrogen, some showed differences from baseline, and some showed various summary statistics of breath hydrogen over different time periods. There was no standard objective measure of symptoms such as a Likert scale. Instead, symptoms were expressed in various ways (number of instances, scoring systems, or sole mention in text format). For these reasons, a meta-analysis could not be performed. This review could be further criticized because authors were not directly contacted for raw data for a potential meta-analysis.

Recommendations from this review

Several recommendations can be extracted from the results of this review.

First, probiotics in general do not reduce lactose intolerance (SOR: A). However, some evidence suggests that specific strains and concentrations are effective (SOR: B).

Second, there were enough positive treatment arms to suggest that some individuals will, for unknown reasons, have their symptoms eliminated or reduced with probiotics (SOR: B). It is reasonable, therefore, for clinicians to simply tell patients to “try it.” For a more objective analysis, an n-of-1 trial could be used.²¹ Clinicians will have to keep in mind that many people presumed to have lactose intolerance do not meet standard diagnostic criteria when objectively assessed.

Third, several strategies are available to lactose-intolerant persons (SOR: C). Yogurt, lactase enzymes, lactose-free or lactose-reduced products, specific foods, and probiotics selective for strain, concentration, and preparation are all supported by evidence. Onwulata compared results of probiotic milk, lactase tablets plus milk, hydrolyzed lactose milk, and yogurt with that of whole milk. Only yogurt and hydrolyzed lactose milk yielded significantly lower breath hydrogen results. Six of 10 patients reported symptoms with probiotic milk, 3 of 10 with lactase tablets, 1 of 10 with hydrolyzed milk, and no symptoms were reported with yogurt.

Dehkordi showed that probiotic milk had no effect on breath hydrogen results, but his treatment arm of cornflakes with whole milk did significantly affect results. McDonough found that when sweet acidophilus milk was sonicated to release intracellular lactase from the bacterial cells, a significant change in breath hydrogen resulted. Unfortunately, neither Dehkordi nor McDonough measured symptoms in their studies to specify patient-oriented outcomes.

Fourth, many individuals with symptoms of lactose intolerance do not meet the definition of diagnosis as measured by breath hydrogen testing (SOR: B). All clinical trials in this review declined subject enrollment if lactose intolerance symptoms were unconfirmed by breath hydrogen testing, thereby accepting only true positives.

There are several reasons why probiotic supplementation may be superior to commercial lactase supplementation. Patients have varied responses to lactase supplementation with meals, and different preparations may be more or less effective for the same quantity of lactose ingested.²² Also, as mentioned earlier, other research supports the role of probiotics in preventing diarrheal illness, treating irritable bowel syndrome and inflammatory bowel disease, and possibly benefiting persons with atopic disease. Finally, if lactase-producing probiotics are clinically effective and can also adhere to the intestinal lining, patients may experience prolonged reduction or remission of symptoms without the need to ingest any tablets with meals.

Two of the 10 studies (Newcomer, Kim) examined long-term probiotic use for 1 and 2 weeks, respectively. Newcomer measured only symptoms, showing no significant difference between L acidophilus milk and unaltered milk. Kim found that 2 of 3 L acidophilus concentrations significantly decreased breath hydrogen results, but the study did not measure symptoms. We can infer a negative patient-oriented outcome of long-term probiotic intervention based on these 2 trials. However, this domain of chronic probiotic use to reduce lactose intolerance would benefit from additional studies for comparison.

In conclusion, probiotic supplementation in general was not effective at reducing lactose intolerance of adults. Some evidence suggests that certain strains, concentrations, and preparations are effective. Clinicians could discuss probiotic supplementation with patients as an alternative treatment. There were enough positive treatment arms to suggest there may be individuals who respond to probiotics. Further studies are needed to determine specific probiotic relationships. The best studies would be those using crossover randomized double-blind design of selected probiotic strains and concentrations and objectively measuring breath hydrogen and symptoms with a long enough wash-out period to eliminate the chance of gut colonization.

Acknowledgments

Material in this article has been previously presented at the following: “Probiotic Supplementation as Treatment for Lactose Intolerance: a Systematic Review,” Fellows works-in-progress poster presentation at the STFM 36th Annual Conference, Atlanta, GA, September 2003, Kara M. Levri, Kari Ketvertis, Mark Deramo, Joel H. Merenstein, Frank D’Amico; “Probiotic Supplementation as Treatment for Lactose Intolerance: A Systematic Review,” Grand Professor Rounds, UPMC St. Margaret, Pittsburgh, Pa, June 2003, Kara M. Levri, Kari Ketvertis, Mark Deramo; “Probiotic Supplementation as Treatment for Lactose Intolerance: a Systematic Review,” Pennsylvania Academy of Family Physicians Research Day, Philadelphia, Pa, April 2003, Kara M. Levri.

CORRESPONDING AUTHOR
Kara M. Levri, MD, MPH, UPMC St. Margaret, 3937 Butler Street, Pittsburgh, PA 15201. E-mail: [email protected].

Prostate cancer screening in asymptomatic men remains controversial, and it is difficult to present its benefits and risks quickly in a way that is understandable to patients. Yet many expert groups agree that physicians should enter into a mutual decision-making process with patients.^1-3

This article reviews the latest information relevant to the controversy, offers “talking points” for family physicians to use when discussing screening with patients, and lists websites that patients may find helpful when making a decision about prostate cancer screening.

For this review, we searched for recent articles that are generalizable to a primary care population and of the highest evidence level available. We preferentially discuss population-based studies, studies from randomized trials of screening, and meta-analyses, rather than results that are hospital- or clinic-based. For a complete systematic review of this topic (from 2002), readers are referred to one conducted for the Agency for Healthcare Research and Quality.⁴ (See Scope of the problem).

Key components of the controversy

How effective is screening?

A good screening test does 2 things. First, it detects a disease earlier than it would be detected with no screening at all, and it does so with sufficient accuracy to avoid a large number of false-positive and false-negative results.

Second, it leads to treatment of early disease that will likely produce a more favorable health outcome than waiting to treat patients who have signs and symptoms of disease.⁹ Unfortunately it is still unclear whether screening tests for prostate cancer meet these 2 criteria.

Skewed numbers. Yes, estimates of false-positive and false-negative results are available from numerous studies of different populations. However, in most studies, only men with abnormal test results receive a biopsy. Men with normal screening test results are not biopsied. Therefore the number of false negatives (and true negatives) is unknown. Furthermore, these estimates are often based on patients from urology clinics, a group more likely to have disease, thereby increasing the positive predictive value of a given screening test.

Whether current screening methods—in particular, prostate-specific antigen (PSA)—identify prostate cancers destined to become clinically relevant is also unknown. If screening does identify such cancers, a decrease in prostate cancer mortality among men who were screened is expected. If it does not, overdiagnosis and treatment of clinically insignificant cancers will negatively impact the quality of men’s lives without extending their life spans.

Clinical variability of the disease

The natural history of prostate cancer is uncertain. If cancer is left unidentified or untreated, more men will die with prostate cancer than of prostate cancer.

Clinically, prostate cancer ranges from an asymptomatic slow-growing tumor to an aggressive cancer with painful metastases. Treatment may be unnecessary at one end of the spectrum and palliative at the other.

The goal of screening is to identify slow-growing tumors destined to extend beyond the prostate while they are confined to the prostate and amenable to treatment, thereby decreasing the risk of prostate cancer morbidity and death.

Usually low morbidity. For a 50-year-old man, the risk of being diagnosed with prostate cancer by age 80 years is 15%; however, the same man has a 1.4% chance of dying of prostate cancer over that 30-year period.⁷ This 10-fold difference shows that prostate cancer usually is not a fatal illness. Another indication of the often benign nature of the disease is the high percentage of prostate cancers identified at surgery for bladder cancer; up to 40% of specimens contain unsuspected prostate cancer (level of evidence [LOE]: 2c).^10,11

Most clinical diagnoses (80%) and prostate cancer deaths (90%) occur among men older than 65 years;⁶ the median age at diagnosis is 72 years.¹² More than 75% of men older than 85 years will have histological prostate cancer (LOE: 2c).¹³ Many men live with their disease for more than 10 years, but do not die of it (LOE: 2c).¹² Additionally, a review of several decision analyses indicates that men 75 years of age and older are not likely to benefit from screening and aggressive treatment (LOE: 2a).¹⁴

Hence the recommendation: if performing prostate cancer screening, limit to men with greater than 10 years life expectancy.¹⁵

Details of screening tests

Digital rectal examination insufficient

Digital rectal examination (DRE)—palpating the prostate gland to determine size and consistency—is one screening tool for prostate cancer, usually performed in conjunction with PSA testing.¹⁵ It is not a difficult or expensive test, but its reproducibility is only fair, even among experienced urologists (LOE: 2b).¹⁶

The sensitivity and specificity of DRE can only be estimated because men with a normal finding on DRE are not routinely biopsied in any studies (TABLE 1).^17,18 One of two pertinent meta-analyses¹⁸ included studies that followed men with a negative DRE finding for development of prostate cancer (LOE: 2a). Both meta-analyses of DRE as a screening tool found that the included studies were heterogeneous in their study populations and definition of abnormal DRE test result (LOE: 2a). The positive predictive value (PPV) of DRE was 28% in one meta-analysis and 18% in the other.

TABLE 1
Characteristics of screening tests for prostate cancer

Prostate-specific antigen: Improving its clinical usefulness

Prostate-specific antigen (PSA), first detected in serum in 1979, is a protein produced by prostate epithelial cells. It was originally used to follow men treated for prostate cancer for evidence of recurrence. In the late 1980s, it became widely used in the US to screen for prostate cancer.

An elevated PSA level is suggestive but not diagnostic of prostate cancer. Elevated levels also occur with advancing age, increased prostate size, and prostatitis, and following ejaculation. Prostate manipulation such as biopsy and surgery (but not digital examination) also elevates PSA.

Customary cutpoint. An abnormal serum PSA level is commonly regarded as 4 ng/mL or greater. At this cutpoint, most studies report sensitivity for cancer of around 70%, with more variability in specificity (TABLE 1). Again, in most studies that report sensitivity and specificity, men with a PSA level less than 4 ng/mL did not undergo prostate biopsy; therefore, the number of false negatives and true negatives are only estimates.

In nested case-control studies of longitudinal cohorts, eligible cases were defined by the length of time between an abnormal PSA result and prostate cancer diagnosis, while controls were men who were not diagnosed with prostate cancer during the same time period (however, a biopsy was not usually performed). The PPV of an abnormal PSA level is estimated at 25% to 37%. As a comparison, the PPV of a positive mammogram finding for women 50 to 59 years is 4% to 9%, and 10% to 19% for women age 60 to 69.²¹

Suggested strategies to improve PSA accuracy. Approximately 70% of men with an elevated serum PSA level do not have cancer. To decrease the number of unnecessary biopsies, experts have suggested several strategies:

• using DRE with PSA
• calculating a ratio of free PSA (unbound to protein) or complexed PSA (bound to protein) to total PSA
• measuring PSA density, which incorporates the volume of the prostate gland and is subject to observer variability in prostate volume measurement
• recording PSA velocity, which is the annual rate of change in PSA level and requires 3 or more measurements.

Revise the cutpoint? The cutpoint of 4 ng/mL has been deemed too high by some clinicians. A recent report of men enrolled in a large prostate cancer prevention trial found that among the 9459 men receiving placebo, 2950 had a PSA level of 4 ng/mL or less and had normal prostates on DRE (LOE: 1b).²² All 2950 underwent a prostate biopsy; 449 (15.2%) were positive for cancer. Nearly 30% of those had a PSA level of 2 ng/mL or less.

Approximately 25% of tumors in men referred for biopsy because of abnormal PSA or DRE findings are thought to be discovered by chance due to the biopsy procedure and the high prevalence of disease (LOE: 2c).²³ Furthermore, a recent study indicates that annual PSA fluctuation is substantial; 45% of men who initially had a value of 4 ng/mL or greater, subsequently had a normal level (LOE: 2b).²⁴ Isolated abnormal levels should be confirmed before referral for biopsy.

Identifying clinically relevant cancers

The continued controversy around PSA screening relates to the potential over-diagnosis of localized prostate cancers that are not likely to become clinically significant. The ideal screening test would predictably identify cancers likely to progress.

Screening over-detects

Several computer simulations have estimated the amount of over-detection of prostate cancer. The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry data demonstrated that the proportion of prostate cancer found through PSA testing that otherwise would not have been diagnosed in the patient’s lifetime was 29% for white men and 44% for black men (LOE: 2c).²⁵

An Italian study found that the proportional excess of cancers detected by screening over those that would have been expected in the absence of screening is greater than 50% (LOE: 2c).²⁶

Finally, a model based on results from the European randomized study of prostate cancer screening estimated that a screening program with a 4-year interval from age 55 to 67 has an over-detection rate of 48% (cancers that would not have been diagnosed in the absence of screening) (LOE: 2c).²⁷ Additionally, the authors determined that such screening might advance prostate cancer diagnosis by at least 10 years. Previous estimates of diagnosis lead time have been in the 5- to 7-year range (LOE: 2b).²⁸ These findings indicate that screening intervals of 2 to 4 years are unlikely to cause a loss of sensitivity.

Spread of tumor

Spread of the tumor beyond the prostate capsule is a poor prognostic sign.²⁹ Unfortunately, this occurrence is often not known until surgery, and the result usually is an “up-staging” between clinical diagnosis and pathological diagnosis. Nevertheless, most cancers (86%) diagnosed between 1992 and 1999 were localized to the prostate.⁶ Because these cancers have not spread beyond the prostate at the time of diagnosis, they are more likely to be curable. They are also more likely to represent tumors that may grow so slowly that the host will die of something other than prostate cancer.

Gleason score

Gleason score is another predictor of cancers destined to become clinically relevant (FIGURE 1). A Gleason score of 7 or greater denotes moderate to poor cellular differentiation and indicates a greater potential for progression than lower Gleason values.²⁹ A recent long-term follow-up report on a cohort of men with localized cancer treated conservatively demonstrated that men with low-grade tumors (Gleason score 2–4) have a minimal risk of dying from prostate cancer after 20 years, while men with high-grade tumors (Gleason score of 8–10) have high probability of prostate cancer death within 10 years of diagnosis (LOE: 2b).³⁰ Ecological³¹ and clinical studies³² indicate that a substantial proportion of PSA-detected cancers are moderately differentiated. This is especially true in a first round of screening; as in the European randomized study of screening, where 36% of cancers were Gleason score 7 or higher (LOE: 1b).³³

FIGURE 1
Calculating the Gleason score

The Gleason score is based on the level of differentiation and growth pattern of prostate cancer cells. Cancer cells that closely resemble the normal prostate cells when viewed under low-power magnification are well differentiated. Cancer cells that do not retain the structure of the surrounding normal cells are poorly differentiated. Scores range from 1 to 5.

In examining histologic samples of a patient’s prostate tissue, the pathologist will identify the 2 most commonly occurring patterns (types of differentiation) among the cancer cells and assign a numerical value to each pattern. The 2 numbers are then added to yield the final Gleason score. If a single pattern dominates, the pathologist will simply double the corresponding value.

Total scores range from 2 to 10. Scores in the range of 2–4 are considered well-differentiated, 5–7 are moderately differentiated, and 8–10 are poorly differentiated. In general, the higher the score, the worse the prognosis. Men with well-differentiated tumors that are treated conservatively have minimal risk of dying from prostate cancer.

Is declining mortality a sign of screening success?

Prostate cancer mortality has been declining since the mid-1990s in numerous parts of the world; the US,^6,34 Canada,³⁵ Australia,³⁶ and the United Kingdom³⁷ have all reported a reduction in the rate of prostate cancer deaths. Advocates of PSA screening point to this trend as evidence of the effectiveness of screening. But such ecological data are difficult to interpret. For instance, although much less PSA screening is performed in the UK, mortality trends are similar to those in the US where PSA testing has been used more widely.³⁸

Aggressive screening not necessarily the reason. In the US, 2 geographic areas—Seattle, Washington and Connecticut—provided a natural experiment to compare the effect of aggressive screening on prostate cancer mortality (LOE: 2c).³⁹ Although more aggressive screening and treatment took place in the Seattle area, prostate cancer mortality rates were similar to those in Connecticut over 11 years of follow-up. Similarly, in a study in British Columbia, prostate cancer mortality from 1985 to 1999 was not associated with the intensity of PSA screening (LOE: 2c).⁴⁰

Other possible explanations. If the mortality decrease is not related to PSA screening, what could cause it? One explanation is “attribution bias.” Death certificate misattribution of cause of death from prostate cancer may partially explain the pattern of increasing, then decreasing mortality rates (LOE: 2c).⁴¹ Improvement in prostate cancer treatment, especially for advanced stage, and in particular hormone therapy, is another possible explanation for the decreasing prostate cancer mortality (LOE: 2c).^14,42

Benefits of screening

The benefit of any effective screening test is a decrease in the risk of the screened-disease mortality. The best way to demonstrate decreased risk is through a randomized controlled study of the screening test, and 2 such trials are underway for prostate cancer. In the meantime, a decision model estimates that aggressive treatment of organ-confined disease potentially adds 3 years of life for men in their fifties, 1.5 years for men in their sixties, and 0.4 years for men in their seventies (LOE: 2c).³

Others have concluded that 25 men with clinically detected prostate cancer would need to be treated with surgery to prevent 1 prostate cancer death during a 6-year period, without evidence that quality of life is improved (LOE: 2c).⁴³

Consider quality of life. With uncertainty surrounding improvement in the quantity of life as a result of prostate cancer screening, improved quality of life may be an issue for patients. Focus group research has demonstrated that some patients believe it is better to know if a cancer is present than to wonder if it will be diagnosed when it is too late for cure.⁴⁴

General quality of life has been found to be similar among men treated for prostate cancer and age-matched controls without prostate cancer; however, urinary, sexual, and bowel function vary substantially between treated and untreated men and by treatment type (LOE: 3b) (TABLE 2).^45,46 In general, men treated with radical prostatectomy and brachytherapy often report better general quality of life than men who undergo radiation treatment, despite having more urinary and sexual problems (LOE: 2b).^47,48

TABLE 2
Estimates of risk associated with specific prostate cancer treatments 12 months or more after treatment

Harms of screening

The chances of undergoing a biopsy based on an abnormal screening PSA are estimated at 15% to 40% depending on the patient’s age (FIGURE 2).³ There are adverse effects associated with transrectal biopsy of the prostate. In 2 large population-basedstudies of screening, the most frequent complications were hematuria and hematospermia (LOE: 1b, 2b) (TABLE 3), with more serious consequences such as sepsis and hospitalization occurring in fewer than 1% of patients. A study of 100 screened men with an abnormal PSA who underwent prostate biopsy found that although 69% felt moderate to severe pain with the biopsy, 80% would be willing to undergo a repeat biopsy (LOE: 1b).⁴⁹

Treatment options. If the biopsy result is positive, the most common treatment options for localized cancer—which represents over 80% of all prostate cancers diagnosed⁶—include radical prostatectomy, external beam radiation therapy, brachytherapy (internal radiation therapy) or expectant management (watchful waiting). Population-based studies have reported outcomes for these treatment options (TABLE 2). Outcomes derived from hospital-based series of other prostate cancer treatments, such as cryotherapy and 3-dimensional radiation, are available, but the estimates often reflect the experience of only a few hospitals and are not representative of other facilities. Androgen ablation is the standard treatment for metastatic prostate cancer.

Untoward effects of treatment. Approximately 60% of radical prostatectomy patients report some incontinence 12 months or more after surgery (LOE: 2b),^50,51 and about 30% of patients need to wear pads for urine leakage (LOE: 2b).^50-53 Men undergoing radiation therapy have less urinary incontinence, but about 30% complain of diarrhea and loose stools (LOE: 2b).^51,52 Both therapies are associated with a high percentage of erectile dysfunction: approximately 60% of radiation therapy patients and 75% of surgery patients report their erections are not firm enough for intercourse (LOE: 2b).^51,52

Expectant management (following the cancer with regular PSA and ultrasound testing) is sometimes difficult to “sell” to patients whose fear of cancer dictates that the only logical response is to “cut it out.”⁴⁴ A recent randomized trial indicated that radical prostatectomy lowers prostate cancer mortality, local progression, distant metastasis, and overall survival as compared with watchful waiting over a median of 8.2 years of follow-up (LOE: 1b).⁵⁴ However, these results may have little relevance to prostate cancer screening since only 5% of the cancers were screen-detected and 76% were palpable.

FIGURE 2
Yield of screening 1000 men for prostate cancer

TABLE 3
Percentage of patients with specific complication of transrectal prostate biopsy

Recommendations from expert groups

Different expert groups have conflicting recommendations. Both the American Urological Association and the American Cancer Society recommend annual PSA screening starting at age 50 for most men; younger if risk factors are present. Groups that are evidence based tend to recommend a shared decision making process with patients. The AAFP and American College of Physicians advise physicians to counsel men on the known risks and uncertain benefits of screening for prostate cancer. The US Preventive Services Task Force 2002 update concluded that evidence is insufficient to recommend for or against routine screening for prostate cancer using PSA or DRE. The National Cancer Institute cites a lack of evidence to determine a net benefit for PSA or DRE screening.

When will we know more?

Only 1 randomized controlled trial of prostate cancer screening has been completed⁵⁵: 46,193 men were randomized to either PSA and DRE or no screening from 1989 to 1996. The study had methodological problems; for instance, only 23% of the group randomized to screening was screened. The investigators in the trial have interpreted its results as demonstrating a decrease in prostate cancer deaths in the screened group compared with the unscreened group (15 vs 48.7 per 100,000 man-years).⁵⁵ Others have criticized the statistical analysis and calculated the results using an “intent to screen” analysis, finding no difference in prostate cancer deaths between the 2 groups.^3,56

Two randomized controlled trials of screening are ongoing: the National Cancer Institute’s Prostate, Lung, Colon, Ovarian (PLCO) Screening Trial⁵⁷ and the European Randomized Study of Screening for Prostate Cancer.⁵⁸ Both were started in the mid-1990s and will not have results available for a few more years. Also underway is a randomized trial of intervention (radical prostatectomy) versus expectant management, called the Prostate Cancer Intervention Versus Observation Trial (PIVOT).⁵⁹

Counseling recommendations

However, providing men with information on prostate cancer screening before they discussed it with their family physician, rather than after the visit, resulted in patients having a significantly more active role in making a screening decision, and lower levels of decisional conflict (LOE: 2b).⁶¹ Informational pamphlets are available through the AAFP and CDC websites listed in TABLE 4. Additional websites containing prostate cancer screening information are found in TABLE 4. We also provide a bullet item list of key points for discussion with patients (TABLE 5), which can be used along with the balance sheet provided here (TABLE 2).

Shared decision-making is not an easy or quick process. Yet, the majority of patients will benefit from the discussion, regardless of the final decision. Of course, there are instances when a shared decision-making process is well-documented, and still results in an undesirable outcome;⁶² however, while the evidence for screening remains controversial, patients have the right to know that those controversies exist and why they exist.

TABLE 4
Useful websites for patients to find prostate cancer screening information

TABLE 5
Talking points for patients and physicians

CORRESPONDING AUTHOR
Kendra Schwartz, MD, MSPH, 101 E. Alexandrine, Detroit, MI 48201, E-mail: [email protected]

Prostate cancer screening in asymptomatic men remains controversial, and it is difficult to present its benefits and risks quickly in a way that is understandable to patients. Yet many expert groups agree that physicians should enter into a mutual decision-making process with patients.^1-3

This article reviews the latest information relevant to the controversy, offers “talking points” for family physicians to use when discussing screening with patients, and lists websites that patients may find helpful when making a decision about prostate cancer screening.

For this review, we searched for recent articles that are generalizable to a primary care population and of the highest evidence level available. We preferentially discuss population-based studies, studies from randomized trials of screening, and meta-analyses, rather than results that are hospital- or clinic-based. For a complete systematic review of this topic (from 2002), readers are referred to one conducted for the Agency for Healthcare Research and Quality.⁴ (See Scope of the problem).

Key components of the controversy

How effective is screening?

A good screening test does 2 things. First, it detects a disease earlier than it would be detected with no screening at all, and it does so with sufficient accuracy to avoid a large number of false-positive and false-negative results.

Second, it leads to treatment of early disease that will likely produce a more favorable health outcome than waiting to treat patients who have signs and symptoms of disease.⁹ Unfortunately it is still unclear whether screening tests for prostate cancer meet these 2 criteria.

Skewed numbers. Yes, estimates of false-positive and false-negative results are available from numerous studies of different populations. However, in most studies, only men with abnormal test results receive a biopsy. Men with normal screening test results are not biopsied. Therefore the number of false negatives (and true negatives) is unknown. Furthermore, these estimates are often based on patients from urology clinics, a group more likely to have disease, thereby increasing the positive predictive value of a given screening test.

Whether current screening methods—in particular, prostate-specific antigen (PSA)—identify prostate cancers destined to become clinically relevant is also unknown. If screening does identify such cancers, a decrease in prostate cancer mortality among men who were screened is expected. If it does not, overdiagnosis and treatment of clinically insignificant cancers will negatively impact the quality of men’s lives without extending their life spans.

Clinical variability of the disease

The natural history of prostate cancer is uncertain. If cancer is left unidentified or untreated, more men will die with prostate cancer than of prostate cancer.

Clinically, prostate cancer ranges from an asymptomatic slow-growing tumor to an aggressive cancer with painful metastases. Treatment may be unnecessary at one end of the spectrum and palliative at the other.

The goal of screening is to identify slow-growing tumors destined to extend beyond the prostate while they are confined to the prostate and amenable to treatment, thereby decreasing the risk of prostate cancer morbidity and death.

Usually low morbidity. For a 50-year-old man, the risk of being diagnosed with prostate cancer by age 80 years is 15%; however, the same man has a 1.4% chance of dying of prostate cancer over that 30-year period.⁷ This 10-fold difference shows that prostate cancer usually is not a fatal illness. Another indication of the often benign nature of the disease is the high percentage of prostate cancers identified at surgery for bladder cancer; up to 40% of specimens contain unsuspected prostate cancer (level of evidence [LOE]: 2c).^10,11

Most clinical diagnoses (80%) and prostate cancer deaths (90%) occur among men older than 65 years;⁶ the median age at diagnosis is 72 years.¹² More than 75% of men older than 85 years will have histological prostate cancer (LOE: 2c).¹³ Many men live with their disease for more than 10 years, but do not die of it (LOE: 2c).¹² Additionally, a review of several decision analyses indicates that men 75 years of age and older are not likely to benefit from screening and aggressive treatment (LOE: 2a).¹⁴

Hence the recommendation: if performing prostate cancer screening, limit to men with greater than 10 years life expectancy.¹⁵

Details of screening tests

Digital rectal examination insufficient

Digital rectal examination (DRE)—palpating the prostate gland to determine size and consistency—is one screening tool for prostate cancer, usually performed in conjunction with PSA testing.¹⁵ It is not a difficult or expensive test, but its reproducibility is only fair, even among experienced urologists (LOE: 2b).¹⁶

The sensitivity and specificity of DRE can only be estimated because men with a normal finding on DRE are not routinely biopsied in any studies (TABLE 1).^17,18 One of two pertinent meta-analyses¹⁸ included studies that followed men with a negative DRE finding for development of prostate cancer (LOE: 2a). Both meta-analyses of DRE as a screening tool found that the included studies were heterogeneous in their study populations and definition of abnormal DRE test result (LOE: 2a). The positive predictive value (PPV) of DRE was 28% in one meta-analysis and 18% in the other.

TABLE 1
Characteristics of screening tests for prostate cancer

Prostate-specific antigen: Improving its clinical usefulness

Prostate-specific antigen (PSA), first detected in serum in 1979, is a protein produced by prostate epithelial cells. It was originally used to follow men treated for prostate cancer for evidence of recurrence. In the late 1980s, it became widely used in the US to screen for prostate cancer.

An elevated PSA level is suggestive but not diagnostic of prostate cancer. Elevated levels also occur with advancing age, increased prostate size, and prostatitis, and following ejaculation. Prostate manipulation such as biopsy and surgery (but not digital examination) also elevates PSA.

Customary cutpoint. An abnormal serum PSA level is commonly regarded as 4 ng/mL or greater. At this cutpoint, most studies report sensitivity for cancer of around 70%, with more variability in specificity (TABLE 1). Again, in most studies that report sensitivity and specificity, men with a PSA level less than 4 ng/mL did not undergo prostate biopsy; therefore, the number of false negatives and true negatives are only estimates.

In nested case-control studies of longitudinal cohorts, eligible cases were defined by the length of time between an abnormal PSA result and prostate cancer diagnosis, while controls were men who were not diagnosed with prostate cancer during the same time period (however, a biopsy was not usually performed). The PPV of an abnormal PSA level is estimated at 25% to 37%. As a comparison, the PPV of a positive mammogram finding for women 50 to 59 years is 4% to 9%, and 10% to 19% for women age 60 to 69.²¹

Suggested strategies to improve PSA accuracy. Approximately 70% of men with an elevated serum PSA level do not have cancer. To decrease the number of unnecessary biopsies, experts have suggested several strategies:

• using DRE with PSA
• calculating a ratio of free PSA (unbound to protein) or complexed PSA (bound to protein) to total PSA
• measuring PSA density, which incorporates the volume of the prostate gland and is subject to observer variability in prostate volume measurement
• recording PSA velocity, which is the annual rate of change in PSA level and requires 3 or more measurements.

Revise the cutpoint? The cutpoint of 4 ng/mL has been deemed too high by some clinicians. A recent report of men enrolled in a large prostate cancer prevention trial found that among the 9459 men receiving placebo, 2950 had a PSA level of 4 ng/mL or less and had normal prostates on DRE (LOE: 1b).²² All 2950 underwent a prostate biopsy; 449 (15.2%) were positive for cancer. Nearly 30% of those had a PSA level of 2 ng/mL or less.

Approximately 25% of tumors in men referred for biopsy because of abnormal PSA or DRE findings are thought to be discovered by chance due to the biopsy procedure and the high prevalence of disease (LOE: 2c).²³ Furthermore, a recent study indicates that annual PSA fluctuation is substantial; 45% of men who initially had a value of 4 ng/mL or greater, subsequently had a normal level (LOE: 2b).²⁴ Isolated abnormal levels should be confirmed before referral for biopsy.

Identifying clinically relevant cancers

The continued controversy around PSA screening relates to the potential over-diagnosis of localized prostate cancers that are not likely to become clinically significant. The ideal screening test would predictably identify cancers likely to progress.

Screening over-detects

Several computer simulations have estimated the amount of over-detection of prostate cancer. The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry data demonstrated that the proportion of prostate cancer found through PSA testing that otherwise would not have been diagnosed in the patient’s lifetime was 29% for white men and 44% for black men (LOE: 2c).²⁵

An Italian study found that the proportional excess of cancers detected by screening over those that would have been expected in the absence of screening is greater than 50% (LOE: 2c).²⁶

Finally, a model based on results from the European randomized study of prostate cancer screening estimated that a screening program with a 4-year interval from age 55 to 67 has an over-detection rate of 48% (cancers that would not have been diagnosed in the absence of screening) (LOE: 2c).²⁷ Additionally, the authors determined that such screening might advance prostate cancer diagnosis by at least 10 years. Previous estimates of diagnosis lead time have been in the 5- to 7-year range (LOE: 2b).²⁸ These findings indicate that screening intervals of 2 to 4 years are unlikely to cause a loss of sensitivity.

Spread of tumor

Spread of the tumor beyond the prostate capsule is a poor prognostic sign.²⁹ Unfortunately, this occurrence is often not known until surgery, and the result usually is an “up-staging” between clinical diagnosis and pathological diagnosis. Nevertheless, most cancers (86%) diagnosed between 1992 and 1999 were localized to the prostate.⁶ Because these cancers have not spread beyond the prostate at the time of diagnosis, they are more likely to be curable. They are also more likely to represent tumors that may grow so slowly that the host will die of something other than prostate cancer.

Gleason score

Gleason score is another predictor of cancers destined to become clinically relevant (FIGURE 1). A Gleason score of 7 or greater denotes moderate to poor cellular differentiation and indicates a greater potential for progression than lower Gleason values.²⁹ A recent long-term follow-up report on a cohort of men with localized cancer treated conservatively demonstrated that men with low-grade tumors (Gleason score 2–4) have a minimal risk of dying from prostate cancer after 20 years, while men with high-grade tumors (Gleason score of 8–10) have high probability of prostate cancer death within 10 years of diagnosis (LOE: 2b).³⁰ Ecological³¹ and clinical studies³² indicate that a substantial proportion of PSA-detected cancers are moderately differentiated. This is especially true in a first round of screening; as in the European randomized study of screening, where 36% of cancers were Gleason score 7 or higher (LOE: 1b).³³

FIGURE 1
Calculating the Gleason score

The Gleason score is based on the level of differentiation and growth pattern of prostate cancer cells. Cancer cells that closely resemble the normal prostate cells when viewed under low-power magnification are well differentiated. Cancer cells that do not retain the structure of the surrounding normal cells are poorly differentiated. Scores range from 1 to 5.

In examining histologic samples of a patient’s prostate tissue, the pathologist will identify the 2 most commonly occurring patterns (types of differentiation) among the cancer cells and assign a numerical value to each pattern. The 2 numbers are then added to yield the final Gleason score. If a single pattern dominates, the pathologist will simply double the corresponding value.

Total scores range from 2 to 10. Scores in the range of 2–4 are considered well-differentiated, 5–7 are moderately differentiated, and 8–10 are poorly differentiated. In general, the higher the score, the worse the prognosis. Men with well-differentiated tumors that are treated conservatively have minimal risk of dying from prostate cancer.

Is declining mortality a sign of screening success?

Prostate cancer mortality has been declining since the mid-1990s in numerous parts of the world; the US,^6,34 Canada,³⁵ Australia,³⁶ and the United Kingdom³⁷ have all reported a reduction in the rate of prostate cancer deaths. Advocates of PSA screening point to this trend as evidence of the effectiveness of screening. But such ecological data are difficult to interpret. For instance, although much less PSA screening is performed in the UK, mortality trends are similar to those in the US where PSA testing has been used more widely.³⁸

Aggressive screening not necessarily the reason. In the US, 2 geographic areas—Seattle, Washington and Connecticut—provided a natural experiment to compare the effect of aggressive screening on prostate cancer mortality (LOE: 2c).³⁹ Although more aggressive screening and treatment took place in the Seattle area, prostate cancer mortality rates were similar to those in Connecticut over 11 years of follow-up. Similarly, in a study in British Columbia, prostate cancer mortality from 1985 to 1999 was not associated with the intensity of PSA screening (LOE: 2c).⁴⁰

Other possible explanations. If the mortality decrease is not related to PSA screening, what could cause it? One explanation is “attribution bias.” Death certificate misattribution of cause of death from prostate cancer may partially explain the pattern of increasing, then decreasing mortality rates (LOE: 2c).⁴¹ Improvement in prostate cancer treatment, especially for advanced stage, and in particular hormone therapy, is another possible explanation for the decreasing prostate cancer mortality (LOE: 2c).^14,42

Benefits of screening

The benefit of any effective screening test is a decrease in the risk of the screened-disease mortality. The best way to demonstrate decreased risk is through a randomized controlled study of the screening test, and 2 such trials are underway for prostate cancer. In the meantime, a decision model estimates that aggressive treatment of organ-confined disease potentially adds 3 years of life for men in their fifties, 1.5 years for men in their sixties, and 0.4 years for men in their seventies (LOE: 2c).³

Others have concluded that 25 men with clinically detected prostate cancer would need to be treated with surgery to prevent 1 prostate cancer death during a 6-year period, without evidence that quality of life is improved (LOE: 2c).⁴³

Consider quality of life. With uncertainty surrounding improvement in the quantity of life as a result of prostate cancer screening, improved quality of life may be an issue for patients. Focus group research has demonstrated that some patients believe it is better to know if a cancer is present than to wonder if it will be diagnosed when it is too late for cure.⁴⁴

General quality of life has been found to be similar among men treated for prostate cancer and age-matched controls without prostate cancer; however, urinary, sexual, and bowel function vary substantially between treated and untreated men and by treatment type (LOE: 3b) (TABLE 2).^45,46 In general, men treated with radical prostatectomy and brachytherapy often report better general quality of life than men who undergo radiation treatment, despite having more urinary and sexual problems (LOE: 2b).^47,48

TABLE 2
Estimates of risk associated with specific prostate cancer treatments 12 months or more after treatment

Harms of screening

The chances of undergoing a biopsy based on an abnormal screening PSA are estimated at 15% to 40% depending on the patient’s age (FIGURE 2).³ There are adverse effects associated with transrectal biopsy of the prostate. In 2 large population-basedstudies of screening, the most frequent complications were hematuria and hematospermia (LOE: 1b, 2b) (TABLE 3), with more serious consequences such as sepsis and hospitalization occurring in fewer than 1% of patients. A study of 100 screened men with an abnormal PSA who underwent prostate biopsy found that although 69% felt moderate to severe pain with the biopsy, 80% would be willing to undergo a repeat biopsy (LOE: 1b).⁴⁹

Treatment options. If the biopsy result is positive, the most common treatment options for localized cancer—which represents over 80% of all prostate cancers diagnosed⁶—include radical prostatectomy, external beam radiation therapy, brachytherapy (internal radiation therapy) or expectant management (watchful waiting). Population-based studies have reported outcomes for these treatment options (TABLE 2). Outcomes derived from hospital-based series of other prostate cancer treatments, such as cryotherapy and 3-dimensional radiation, are available, but the estimates often reflect the experience of only a few hospitals and are not representative of other facilities. Androgen ablation is the standard treatment for metastatic prostate cancer.

Untoward effects of treatment. Approximately 60% of radical prostatectomy patients report some incontinence 12 months or more after surgery (LOE: 2b),^50,51 and about 30% of patients need to wear pads for urine leakage (LOE: 2b).^50-53 Men undergoing radiation therapy have less urinary incontinence, but about 30% complain of diarrhea and loose stools (LOE: 2b).^51,52 Both therapies are associated with a high percentage of erectile dysfunction: approximately 60% of radiation therapy patients and 75% of surgery patients report their erections are not firm enough for intercourse (LOE: 2b).^51,52

Expectant management (following the cancer with regular PSA and ultrasound testing) is sometimes difficult to “sell” to patients whose fear of cancer dictates that the only logical response is to “cut it out.”⁴⁴ A recent randomized trial indicated that radical prostatectomy lowers prostate cancer mortality, local progression, distant metastasis, and overall survival as compared with watchful waiting over a median of 8.2 years of follow-up (LOE: 1b).⁵⁴ However, these results may have little relevance to prostate cancer screening since only 5% of the cancers were screen-detected and 76% were palpable.

FIGURE 2
Yield of screening 1000 men for prostate cancer

TABLE 3
Percentage of patients with specific complication of transrectal prostate biopsy

Recommendations from expert groups

Different expert groups have conflicting recommendations. Both the American Urological Association and the American Cancer Society recommend annual PSA screening starting at age 50 for most men; younger if risk factors are present. Groups that are evidence based tend to recommend a shared decision making process with patients. The AAFP and American College of Physicians advise physicians to counsel men on the known risks and uncertain benefits of screening for prostate cancer. The US Preventive Services Task Force 2002 update concluded that evidence is insufficient to recommend for or against routine screening for prostate cancer using PSA or DRE. The National Cancer Institute cites a lack of evidence to determine a net benefit for PSA or DRE screening.

When will we know more?

Only 1 randomized controlled trial of prostate cancer screening has been completed⁵⁵: 46,193 men were randomized to either PSA and DRE or no screening from 1989 to 1996. The study had methodological problems; for instance, only 23% of the group randomized to screening was screened. The investigators in the trial have interpreted its results as demonstrating a decrease in prostate cancer deaths in the screened group compared with the unscreened group (15 vs 48.7 per 100,000 man-years).⁵⁵ Others have criticized the statistical analysis and calculated the results using an “intent to screen” analysis, finding no difference in prostate cancer deaths between the 2 groups.^3,56

Two randomized controlled trials of screening are ongoing: the National Cancer Institute’s Prostate, Lung, Colon, Ovarian (PLCO) Screening Trial⁵⁷ and the European Randomized Study of Screening for Prostate Cancer.⁵⁸ Both were started in the mid-1990s and will not have results available for a few more years. Also underway is a randomized trial of intervention (radical prostatectomy) versus expectant management, called the Prostate Cancer Intervention Versus Observation Trial (PIVOT).⁵⁹

Counseling recommendations

However, providing men with information on prostate cancer screening before they discussed it with their family physician, rather than after the visit, resulted in patients having a significantly more active role in making a screening decision, and lower levels of decisional conflict (LOE: 2b).⁶¹ Informational pamphlets are available through the AAFP and CDC websites listed in TABLE 4. Additional websites containing prostate cancer screening information are found in TABLE 4. We also provide a bullet item list of key points for discussion with patients (TABLE 5), which can be used along with the balance sheet provided here (TABLE 2).

Shared decision-making is not an easy or quick process. Yet, the majority of patients will benefit from the discussion, regardless of the final decision. Of course, there are instances when a shared decision-making process is well-documented, and still results in an undesirable outcome;⁶² however, while the evidence for screening remains controversial, patients have the right to know that those controversies exist and why they exist.

TABLE 4
Useful websites for patients to find prostate cancer screening information

TABLE 5
Talking points for patients and physicians

CORRESPONDING AUTHOR
Kendra Schwartz, MD, MSPH, 101 E. Alexandrine, Detroit, MI 48201, E-mail: [email protected]

Prostate cancer screening in asymptomatic men remains controversial, and it is difficult to present its benefits and risks quickly in a way that is understandable to patients. Yet many expert groups agree that physicians should enter into a mutual decision-making process with patients.^1-3

This article reviews the latest information relevant to the controversy, offers “talking points” for family physicians to use when discussing screening with patients, and lists websites that patients may find helpful when making a decision about prostate cancer screening.

For this review, we searched for recent articles that are generalizable to a primary care population and of the highest evidence level available. We preferentially discuss population-based studies, studies from randomized trials of screening, and meta-analyses, rather than results that are hospital- or clinic-based. For a complete systematic review of this topic (from 2002), readers are referred to one conducted for the Agency for Healthcare Research and Quality.⁴ (See Scope of the problem).

Key components of the controversy

How effective is screening?

A good screening test does 2 things. First, it detects a disease earlier than it would be detected with no screening at all, and it does so with sufficient accuracy to avoid a large number of false-positive and false-negative results.

Second, it leads to treatment of early disease that will likely produce a more favorable health outcome than waiting to treat patients who have signs and symptoms of disease.⁹ Unfortunately it is still unclear whether screening tests for prostate cancer meet these 2 criteria.

Skewed numbers. Yes, estimates of false-positive and false-negative results are available from numerous studies of different populations. However, in most studies, only men with abnormal test results receive a biopsy. Men with normal screening test results are not biopsied. Therefore the number of false negatives (and true negatives) is unknown. Furthermore, these estimates are often based on patients from urology clinics, a group more likely to have disease, thereby increasing the positive predictive value of a given screening test.

Whether current screening methods—in particular, prostate-specific antigen (PSA)—identify prostate cancers destined to become clinically relevant is also unknown. If screening does identify such cancers, a decrease in prostate cancer mortality among men who were screened is expected. If it does not, overdiagnosis and treatment of clinically insignificant cancers will negatively impact the quality of men’s lives without extending their life spans.

Clinical variability of the disease

The natural history of prostate cancer is uncertain. If cancer is left unidentified or untreated, more men will die with prostate cancer than of prostate cancer.

Clinically, prostate cancer ranges from an asymptomatic slow-growing tumor to an aggressive cancer with painful metastases. Treatment may be unnecessary at one end of the spectrum and palliative at the other.

The goal of screening is to identify slow-growing tumors destined to extend beyond the prostate while they are confined to the prostate and amenable to treatment, thereby decreasing the risk of prostate cancer morbidity and death.

Usually low morbidity. For a 50-year-old man, the risk of being diagnosed with prostate cancer by age 80 years is 15%; however, the same man has a 1.4% chance of dying of prostate cancer over that 30-year period.⁷ This 10-fold difference shows that prostate cancer usually is not a fatal illness. Another indication of the often benign nature of the disease is the high percentage of prostate cancers identified at surgery for bladder cancer; up to 40% of specimens contain unsuspected prostate cancer (level of evidence [LOE]: 2c).^10,11

Most clinical diagnoses (80%) and prostate cancer deaths (90%) occur among men older than 65 years;⁶ the median age at diagnosis is 72 years.¹² More than 75% of men older than 85 years will have histological prostate cancer (LOE: 2c).¹³ Many men live with their disease for more than 10 years, but do not die of it (LOE: 2c).¹² Additionally, a review of several decision analyses indicates that men 75 years of age and older are not likely to benefit from screening and aggressive treatment (LOE: 2a).¹⁴

Hence the recommendation: if performing prostate cancer screening, limit to men with greater than 10 years life expectancy.¹⁵

Details of screening tests

Digital rectal examination insufficient

Digital rectal examination (DRE)—palpating the prostate gland to determine size and consistency—is one screening tool for prostate cancer, usually performed in conjunction with PSA testing.¹⁵ It is not a difficult or expensive test, but its reproducibility is only fair, even among experienced urologists (LOE: 2b).¹⁶

The sensitivity and specificity of DRE can only be estimated because men with a normal finding on DRE are not routinely biopsied in any studies (TABLE 1).^17,18 One of two pertinent meta-analyses¹⁸ included studies that followed men with a negative DRE finding for development of prostate cancer (LOE: 2a). Both meta-analyses of DRE as a screening tool found that the included studies were heterogeneous in their study populations and definition of abnormal DRE test result (LOE: 2a). The positive predictive value (PPV) of DRE was 28% in one meta-analysis and 18% in the other.

TABLE 1
Characteristics of screening tests for prostate cancer

Prostate-specific antigen: Improving its clinical usefulness

Prostate-specific antigen (PSA), first detected in serum in 1979, is a protein produced by prostate epithelial cells. It was originally used to follow men treated for prostate cancer for evidence of recurrence. In the late 1980s, it became widely used in the US to screen for prostate cancer.

An elevated PSA level is suggestive but not diagnostic of prostate cancer. Elevated levels also occur with advancing age, increased prostate size, and prostatitis, and following ejaculation. Prostate manipulation such as biopsy and surgery (but not digital examination) also elevates PSA.

Customary cutpoint. An abnormal serum PSA level is commonly regarded as 4 ng/mL or greater. At this cutpoint, most studies report sensitivity for cancer of around 70%, with more variability in specificity (TABLE 1). Again, in most studies that report sensitivity and specificity, men with a PSA level less than 4 ng/mL did not undergo prostate biopsy; therefore, the number of false negatives and true negatives are only estimates.

In nested case-control studies of longitudinal cohorts, eligible cases were defined by the length of time between an abnormal PSA result and prostate cancer diagnosis, while controls were men who were not diagnosed with prostate cancer during the same time period (however, a biopsy was not usually performed). The PPV of an abnormal PSA level is estimated at 25% to 37%. As a comparison, the PPV of a positive mammogram finding for women 50 to 59 years is 4% to 9%, and 10% to 19% for women age 60 to 69.²¹

Suggested strategies to improve PSA accuracy. Approximately 70% of men with an elevated serum PSA level do not have cancer. To decrease the number of unnecessary biopsies, experts have suggested several strategies:

• using DRE with PSA
• calculating a ratio of free PSA (unbound to protein) or complexed PSA (bound to protein) to total PSA
• measuring PSA density, which incorporates the volume of the prostate gland and is subject to observer variability in prostate volume measurement
• recording PSA velocity, which is the annual rate of change in PSA level and requires 3 or more measurements.

Revise the cutpoint? The cutpoint of 4 ng/mL has been deemed too high by some clinicians. A recent report of men enrolled in a large prostate cancer prevention trial found that among the 9459 men receiving placebo, 2950 had a PSA level of 4 ng/mL or less and had normal prostates on DRE (LOE: 1b).²² All 2950 underwent a prostate biopsy; 449 (15.2%) were positive for cancer. Nearly 30% of those had a PSA level of 2 ng/mL or less.

Approximately 25% of tumors in men referred for biopsy because of abnormal PSA or DRE findings are thought to be discovered by chance due to the biopsy procedure and the high prevalence of disease (LOE: 2c).²³ Furthermore, a recent study indicates that annual PSA fluctuation is substantial; 45% of men who initially had a value of 4 ng/mL or greater, subsequently had a normal level (LOE: 2b).²⁴ Isolated abnormal levels should be confirmed before referral for biopsy.

Identifying clinically relevant cancers

The continued controversy around PSA screening relates to the potential over-diagnosis of localized prostate cancers that are not likely to become clinically significant. The ideal screening test would predictably identify cancers likely to progress.

Screening over-detects

Several computer simulations have estimated the amount of over-detection of prostate cancer. The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry data demonstrated that the proportion of prostate cancer found through PSA testing that otherwise would not have been diagnosed in the patient’s lifetime was 29% for white men and 44% for black men (LOE: 2c).²⁵

An Italian study found that the proportional excess of cancers detected by screening over those that would have been expected in the absence of screening is greater than 50% (LOE: 2c).²⁶

Finally, a model based on results from the European randomized study of prostate cancer screening estimated that a screening program with a 4-year interval from age 55 to 67 has an over-detection rate of 48% (cancers that would not have been diagnosed in the absence of screening) (LOE: 2c).²⁷ Additionally, the authors determined that such screening might advance prostate cancer diagnosis by at least 10 years. Previous estimates of diagnosis lead time have been in the 5- to 7-year range (LOE: 2b).²⁸ These findings indicate that screening intervals of 2 to 4 years are unlikely to cause a loss of sensitivity.

Spread of tumor

Spread of the tumor beyond the prostate capsule is a poor prognostic sign.²⁹ Unfortunately, this occurrence is often not known until surgery, and the result usually is an “up-staging” between clinical diagnosis and pathological diagnosis. Nevertheless, most cancers (86%) diagnosed between 1992 and 1999 were localized to the prostate.⁶ Because these cancers have not spread beyond the prostate at the time of diagnosis, they are more likely to be curable. They are also more likely to represent tumors that may grow so slowly that the host will die of something other than prostate cancer.

Gleason score

Gleason score is another predictor of cancers destined to become clinically relevant (FIGURE 1). A Gleason score of 7 or greater denotes moderate to poor cellular differentiation and indicates a greater potential for progression than lower Gleason values.²⁹ A recent long-term follow-up report on a cohort of men with localized cancer treated conservatively demonstrated that men with low-grade tumors (Gleason score 2–4) have a minimal risk of dying from prostate cancer after 20 years, while men with high-grade tumors (Gleason score of 8–10) have high probability of prostate cancer death within 10 years of diagnosis (LOE: 2b).³⁰ Ecological³¹ and clinical studies³² indicate that a substantial proportion of PSA-detected cancers are moderately differentiated. This is especially true in a first round of screening; as in the European randomized study of screening, where 36% of cancers were Gleason score 7 or higher (LOE: 1b).³³

FIGURE 1
Calculating the Gleason score

The Gleason score is based on the level of differentiation and growth pattern of prostate cancer cells. Cancer cells that closely resemble the normal prostate cells when viewed under low-power magnification are well differentiated. Cancer cells that do not retain the structure of the surrounding normal cells are poorly differentiated. Scores range from 1 to 5.

In examining histologic samples of a patient’s prostate tissue, the pathologist will identify the 2 most commonly occurring patterns (types of differentiation) among the cancer cells and assign a numerical value to each pattern. The 2 numbers are then added to yield the final Gleason score. If a single pattern dominates, the pathologist will simply double the corresponding value.

Total scores range from 2 to 10. Scores in the range of 2–4 are considered well-differentiated, 5–7 are moderately differentiated, and 8–10 are poorly differentiated. In general, the higher the score, the worse the prognosis. Men with well-differentiated tumors that are treated conservatively have minimal risk of dying from prostate cancer.

Is declining mortality a sign of screening success?

Prostate cancer mortality has been declining since the mid-1990s in numerous parts of the world; the US,^6,34 Canada,³⁵ Australia,³⁶ and the United Kingdom³⁷ have all reported a reduction in the rate of prostate cancer deaths. Advocates of PSA screening point to this trend as evidence of the effectiveness of screening. But such ecological data are difficult to interpret. For instance, although much less PSA screening is performed in the UK, mortality trends are similar to those in the US where PSA testing has been used more widely.³⁸

Aggressive screening not necessarily the reason. In the US, 2 geographic areas—Seattle, Washington and Connecticut—provided a natural experiment to compare the effect of aggressive screening on prostate cancer mortality (LOE: 2c).³⁹ Although more aggressive screening and treatment took place in the Seattle area, prostate cancer mortality rates were similar to those in Connecticut over 11 years of follow-up. Similarly, in a study in British Columbia, prostate cancer mortality from 1985 to 1999 was not associated with the intensity of PSA screening (LOE: 2c).⁴⁰

Other possible explanations. If the mortality decrease is not related to PSA screening, what could cause it? One explanation is “attribution bias.” Death certificate misattribution of cause of death from prostate cancer may partially explain the pattern of increasing, then decreasing mortality rates (LOE: 2c).⁴¹ Improvement in prostate cancer treatment, especially for advanced stage, and in particular hormone therapy, is another possible explanation for the decreasing prostate cancer mortality (LOE: 2c).^14,42

Benefits of screening

The benefit of any effective screening test is a decrease in the risk of the screened-disease mortality. The best way to demonstrate decreased risk is through a randomized controlled study of the screening test, and 2 such trials are underway for prostate cancer. In the meantime, a decision model estimates that aggressive treatment of organ-confined disease potentially adds 3 years of life for men in their fifties, 1.5 years for men in their sixties, and 0.4 years for men in their seventies (LOE: 2c).³

Others have concluded that 25 men with clinically detected prostate cancer would need to be treated with surgery to prevent 1 prostate cancer death during a 6-year period, without evidence that quality of life is improved (LOE: 2c).⁴³

Consider quality of life. With uncertainty surrounding improvement in the quantity of life as a result of prostate cancer screening, improved quality of life may be an issue for patients. Focus group research has demonstrated that some patients believe it is better to know if a cancer is present than to wonder if it will be diagnosed when it is too late for cure.⁴⁴

General quality of life has been found to be similar among men treated for prostate cancer and age-matched controls without prostate cancer; however, urinary, sexual, and bowel function vary substantially between treated and untreated men and by treatment type (LOE: 3b) (TABLE 2).^45,46 In general, men treated with radical prostatectomy and brachytherapy often report better general quality of life than men who undergo radiation treatment, despite having more urinary and sexual problems (LOE: 2b).^47,48

TABLE 2
Estimates of risk associated with specific prostate cancer treatments 12 months or more after treatment

Harms of screening

The chances of undergoing a biopsy based on an abnormal screening PSA are estimated at 15% to 40% depending on the patient’s age (FIGURE 2).³ There are adverse effects associated with transrectal biopsy of the prostate. In 2 large population-basedstudies of screening, the most frequent complications were hematuria and hematospermia (LOE: 1b, 2b) (TABLE 3), with more serious consequences such as sepsis and hospitalization occurring in fewer than 1% of patients. A study of 100 screened men with an abnormal PSA who underwent prostate biopsy found that although 69% felt moderate to severe pain with the biopsy, 80% would be willing to undergo a repeat biopsy (LOE: 1b).⁴⁹

Treatment options. If the biopsy result is positive, the most common treatment options for localized cancer—which represents over 80% of all prostate cancers diagnosed⁶—include radical prostatectomy, external beam radiation therapy, brachytherapy (internal radiation therapy) or expectant management (watchful waiting). Population-based studies have reported outcomes for these treatment options (TABLE 2). Outcomes derived from hospital-based series of other prostate cancer treatments, such as cryotherapy and 3-dimensional radiation, are available, but the estimates often reflect the experience of only a few hospitals and are not representative of other facilities. Androgen ablation is the standard treatment for metastatic prostate cancer.

Untoward effects of treatment. Approximately 60% of radical prostatectomy patients report some incontinence 12 months or more after surgery (LOE: 2b),^50,51 and about 30% of patients need to wear pads for urine leakage (LOE: 2b).^50-53 Men undergoing radiation therapy have less urinary incontinence, but about 30% complain of diarrhea and loose stools (LOE: 2b).^51,52 Both therapies are associated with a high percentage of erectile dysfunction: approximately 60% of radiation therapy patients and 75% of surgery patients report their erections are not firm enough for intercourse (LOE: 2b).^51,52

Expectant management (following the cancer with regular PSA and ultrasound testing) is sometimes difficult to “sell” to patients whose fear of cancer dictates that the only logical response is to “cut it out.”⁴⁴ A recent randomized trial indicated that radical prostatectomy lowers prostate cancer mortality, local progression, distant metastasis, and overall survival as compared with watchful waiting over a median of 8.2 years of follow-up (LOE: 1b).⁵⁴ However, these results may have little relevance to prostate cancer screening since only 5% of the cancers were screen-detected and 76% were palpable.

FIGURE 2
Yield of screening 1000 men for prostate cancer

TABLE 3
Percentage of patients with specific complication of transrectal prostate biopsy

Recommendations from expert groups

Different expert groups have conflicting recommendations. Both the American Urological Association and the American Cancer Society recommend annual PSA screening starting at age 50 for most men; younger if risk factors are present. Groups that are evidence based tend to recommend a shared decision making process with patients. The AAFP and American College of Physicians advise physicians to counsel men on the known risks and uncertain benefits of screening for prostate cancer. The US Preventive Services Task Force 2002 update concluded that evidence is insufficient to recommend for or against routine screening for prostate cancer using PSA or DRE. The National Cancer Institute cites a lack of evidence to determine a net benefit for PSA or DRE screening.

When will we know more?

Only 1 randomized controlled trial of prostate cancer screening has been completed⁵⁵: 46,193 men were randomized to either PSA and DRE or no screening from 1989 to 1996. The study had methodological problems; for instance, only 23% of the group randomized to screening was screened. The investigators in the trial have interpreted its results as demonstrating a decrease in prostate cancer deaths in the screened group compared with the unscreened group (15 vs 48.7 per 100,000 man-years).⁵⁵ Others have criticized the statistical analysis and calculated the results using an “intent to screen” analysis, finding no difference in prostate cancer deaths between the 2 groups.^3,56

Two randomized controlled trials of screening are ongoing: the National Cancer Institute’s Prostate, Lung, Colon, Ovarian (PLCO) Screening Trial⁵⁷ and the European Randomized Study of Screening for Prostate Cancer.⁵⁸ Both were started in the mid-1990s and will not have results available for a few more years. Also underway is a randomized trial of intervention (radical prostatectomy) versus expectant management, called the Prostate Cancer Intervention Versus Observation Trial (PIVOT).⁵⁹

Counseling recommendations

However, providing men with information on prostate cancer screening before they discussed it with their family physician, rather than after the visit, resulted in patients having a significantly more active role in making a screening decision, and lower levels of decisional conflict (LOE: 2b).⁶¹ Informational pamphlets are available through the AAFP and CDC websites listed in TABLE 4. Additional websites containing prostate cancer screening information are found in TABLE 4. We also provide a bullet item list of key points for discussion with patients (TABLE 5), which can be used along with the balance sheet provided here (TABLE 2).

Shared decision-making is not an easy or quick process. Yet, the majority of patients will benefit from the discussion, regardless of the final decision. Of course, there are instances when a shared decision-making process is well-documented, and still results in an undesirable outcome;⁶² however, while the evidence for screening remains controversial, patients have the right to know that those controversies exist and why they exist.

TABLE 4
Useful websites for patients to find prostate cancer screening information

TABLE 5
Talking points for patients and physicians

CORRESPONDING AUTHOR
Kendra Schwartz, MD, MSPH, 101 E. Alexandrine, Detroit, MI 48201, E-mail: [email protected]

Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.

Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.¹

Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,^2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)⁴:

• pain
• hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
• joint stiffness
• swelling
• autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).

Diagnosis: Watch recovery course over first 9 weeks

Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).⁵ Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).^6,7 The key is to remain alert to deviation from the normal course of recovery.

Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).^6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).⁸

Diagnostic criteria: No consensus

No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.⁹ Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),⁴ experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.^7,10

Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.^4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).^11,12

Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).¹¹Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),¹³ which have been adopted as the standard in the Netherlands, have undergone further study.¹⁴ Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).^11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.

The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.¹² In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.¹¹

Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.^11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.⁴ As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.

Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.^11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.^11,12

However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).^15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.¹⁵

TABLE 1
Diagnostic criteria for CRPS type 1*

TABLE 2
Accuracy of diagnostic criteria for CRPS type 1

TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1

Factors undermining objective evaluation

Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,^1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.

First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.

Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.

Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.

For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),¹⁷ resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.

TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1

Diagnostic instrumentation adds little

Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.

Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,^18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).¹⁴

Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,⁴ subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).^20-22

Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,²³ this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.²⁴ Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing ^25,26 or diffuse uptake of radioisotope,²⁷ and about whether delayed phase scintigraphy is adequate ²⁶ or whether 3-phase scintigraphy is necessary.²⁷

To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.²⁷

In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).²⁷ In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).²⁵ Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).²⁶

Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.

Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)¹³ and for DEXA a sensitivity of 76% (LOE: 2, case-control design).²⁸ No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.

Applying the evidence in practice

CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.

With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.

Preventing CRPS 1

For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).

Base evaluation on history and physical exam

More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.

To diagnose CRPS type 1, first rule out other diseases (FIGURE).⁴ The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.

Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,⁴ osteomyelitis or cellulitis,¹³ polyneuropathy, radiculopathy,¹¹ phlebothrombosis,¹³ and Raynaud’s disease.¹³ Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.

Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.

Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).

ACKNOWLEDGMENTS

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: [email protected].

Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.

Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.¹

Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,^2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)⁴:

• pain
• hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
• joint stiffness
• swelling
• autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).

Diagnosis: Watch recovery course over first 9 weeks

Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).⁵ Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).^6,7 The key is to remain alert to deviation from the normal course of recovery.

Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).^6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).⁸

Diagnostic criteria: No consensus

No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.⁹ Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),⁴ experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.^7,10

Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.^4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).^11,12

Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).¹¹Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),¹³ which have been adopted as the standard in the Netherlands, have undergone further study.¹⁴ Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).^11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.

The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.¹² In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.¹¹

Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.^11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.⁴ As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.

Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.^11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.^11,12

However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).^15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.¹⁵

TABLE 1
Diagnostic criteria for CRPS type 1*

TABLE 2
Accuracy of diagnostic criteria for CRPS type 1

TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1

Factors undermining objective evaluation

Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,^1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.

First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.

Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.

Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.

For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),¹⁷ resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.

TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1

Diagnostic instrumentation adds little

Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.

Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,^18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).¹⁴

Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,⁴ subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).^20-22

Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,²³ this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.²⁴ Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing ^25,26 or diffuse uptake of radioisotope,²⁷ and about whether delayed phase scintigraphy is adequate ²⁶ or whether 3-phase scintigraphy is necessary.²⁷

To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.²⁷

In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).²⁷ In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).²⁵ Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).²⁶

Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.

Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)¹³ and for DEXA a sensitivity of 76% (LOE: 2, case-control design).²⁸ No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.

Applying the evidence in practice

CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.

With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.

Preventing CRPS 1

For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).

Base evaluation on history and physical exam

More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.

To diagnose CRPS type 1, first rule out other diseases (FIGURE).⁴ The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.

Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,⁴ osteomyelitis or cellulitis,¹³ polyneuropathy, radiculopathy,¹¹ phlebothrombosis,¹³ and Raynaud’s disease.¹³ Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.

Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.

Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).

ACKNOWLEDGMENTS

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: [email protected].

Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.

Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.¹

Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,^2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)⁴:

• pain
• hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
• joint stiffness
• swelling
• autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).

Diagnosis: Watch recovery course over first 9 weeks

Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).⁵ Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).^6,7 The key is to remain alert to deviation from the normal course of recovery.

Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).^6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).⁸

Diagnostic criteria: No consensus

No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.⁹ Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),⁴ experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.^7,10

Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.^4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).^11,12

Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).¹¹Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),¹³ which have been adopted as the standard in the Netherlands, have undergone further study.¹⁴ Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).^11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.

The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.¹² In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.¹¹

Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.^11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.⁴ As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.

Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.^11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.^11,12

However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).^15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.¹⁵

TABLE 1
Diagnostic criteria for CRPS type 1*

TABLE 2
Accuracy of diagnostic criteria for CRPS type 1

TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1

Factors undermining objective evaluation

Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,^1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.

First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.

Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.

Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.

For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),¹⁷ resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.

TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1

Diagnostic instrumentation adds little

Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.

Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,^18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).¹⁴

Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,⁴ subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).^20-22

Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,²³ this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.²⁴ Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing ^25,26 or diffuse uptake of radioisotope,²⁷ and about whether delayed phase scintigraphy is adequate ²⁶ or whether 3-phase scintigraphy is necessary.²⁷

To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.²⁷

In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).²⁷ In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).²⁵ Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).²⁶

Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.

Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)¹³ and for DEXA a sensitivity of 76% (LOE: 2, case-control design).²⁸ No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.

Applying the evidence in practice

CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.

With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.

Preventing CRPS 1

For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).

Base evaluation on history and physical exam

More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.

To diagnose CRPS type 1, first rule out other diseases (FIGURE).⁴ The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.

Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,⁴ osteomyelitis or cellulitis,¹³ polyneuropathy, radiculopathy,¹¹ phlebothrombosis,¹³ and Raynaud’s disease.¹³ Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.

Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.

Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).

ACKNOWLEDGMENTS

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: [email protected].

Heart failure is a growing epidemic in the US, estimated to cause at least 20% of all hospitalizations in persons over 65 years of age. It is also the leading inpatient diagnosis among Medicare recipients with this age group.^1,2,3 More than 5 million people in the US have heart failure, with approximately 550,000 new cases diagnosed annually.

Growing epidemiologic evidence suggests that studies of heart failure have underrepresented a large patient population with a natural history different from that of left ventricular (LV) systolic dysfunction.^4-8One third to one half of patients with signs and symptoms of heart failure have preserved left ventricular function (LVF). They are said to have diastolic heart failure (DHF).

Identifying persons with this less-understood form of heart failure can be challenging. Skillful discernment is needed to avoid mistakenly attributing symptoms to other causes. DHF is particularly common among elderly women with hypertension; every patient with signs and symptoms of heart failure should undergo echocardiography to determine LV function.

Though the evidence base for DHF treatment is less well established than it is for systolic heart failure (SHF), data from recent trials have offered a promising direction.

New categorization of heart failure

The relative scopes of DHF and SHF will be better appreciated by understanding how recently developed guidelines have restructured the historical classification of heart failure.

Heart failure is defined by the American College of Cardiology (ACC) and the American Heart Association (AHA) as a complex syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood.⁹ The older terms, low-vs high-output failure, are now regarded as obsolete and have been abandoned in favor of distinguishing between abnormalities of systolic and diastolic function.^10-12

ACC/AHA heart failure staging system

Severity of heart failure symptoms has traditionally been gauged by the New York Heart Association (NYHA) classification system. A criticism of the NYHA scale, however, is that patients may fluctuate in and out of the varying functional classes. To correct this shortcoming of the NYHA scale, the ACC and the AHA devised a new staging system to describe the progression of heart failure.⁹ The premise of this new system is to provide permanence to each sequential progression through the stages of heart failure while complementing the existing NYHA scale.^9,13

New model. Patients with Stage A heart failure are at high risk of developing heart failure based on comorbidities and medical history.

Patients with Stage B heart failure have some component of structural heart disease but are asymptomatic.

Patients with Stage C heart failure have underlying structural abnormalities and have symptoms, or have had symptoms of heart failure in the past.

Patients with Stage D heart failure are refractory to conventional medical therapy and have end-stage symptoms.

TABLE 1 shows how the ACC/AHA Heart Failure Staging System correlates with the NYHA Classification scheme. Family practitioners can use the new heart failure staging system to identify and recognize risk factors for the development of heart failure and then seek to aggressively prevent or reverse them.

TABLE 1
Relationship of the ACC/AHA Heart Failure

Who is at risk for DHF?

Risk factors for the development of DHF include advanced age, female sex, hypertension, and coronary ischemia. Approximately 50% of those older than 70 years who have heart failure have preserved LV function.^14-16 In a large epidemiologic study of elderly patients with heart failure, women were twice as likely as men to have preserved LV function.¹⁷ In examining post-myocardial infarction (MI) patients with heart failure, women and those with smaller infarctions were also more likely to have preserved LV function (odds ratio=1.97; 95% confidence interval [CI], 1.27–3.07).¹⁸

Hypertension is a well known cause of left ventricular hypertrophy (LVH), which is a causal mechanism for DHF.^19,20 Levy et al, in a study of 5143 subjects from the original Framingham Heart Study participants and Framingham Offspring participants, found that hypertension predated the development of heart failure in 91% of cases among patients in this cohort.²¹ In this sample, hypertension also carried the greatest population-attributable risk for the development of heart failure of all risk factors considered (39% in men and 59% in women). Hypertension also had the highest prevalence of all risk factors in this study (60% in men and 62% in women). Untreated hypertension leads to an increasing incidence of LVH and associated diastolic dysfunction. Increased LV mass and stiffness cause noncompliance and abnormal relaxation of the ventricular wall leading to increased diastolic pressures.^4,19-21

Coronary ischemia can also cause diastolic dysfunction.²⁰ Data from the Framingham Heart Study indicate that the prevalence of MI was 10% in hypertensive men and 3% in hypertensive women.²¹ MI is a well known precursor of LV systolic dysfunction; however, the relationship to diastolic dysfunction is less clear. Although the prevalence of MI was associated with a 5- to 6-fold risk for heart failure in Framingham subjects, after adjustment for age and other risk factors, fewer than half of the patients who subsequently developed heart failure had a history of MI. This finding supports the role of untreated hypertension in the pathogenesis of DHF.²¹

Physical examination does not help distinguish between DHF and SHF. Signs and symptoms of both disorders are relatively the same.²² Therefore, the presence of one or more of these risk factors in the setting of heart failure and preserved LV function supports the diagnosis of DHF.^14-17TABLE 2 summarizes known clinical characteristics and features of SHF and DHF. All patients with systolic heart failure have some component of diastolic dysfunction as well.^10,12,23,24

TABLE 2
Characteristics of patients with systolic vs diastolic heart failure

Differentiating systolic and diastolic dysfunction
Etiology	Commonly associated with previous MI; exists concurrently with diastolic dysfunction	Pathogenesis is multifocal; associated more often with systemic hypertension, may exist alone without a component of systolic heart failure
Gender-specific differences	Both sexes affected	More common in women
Age-related differences	All ages affected	More common in elderly patients
Echocardiographic findings	Depressed LVEF <40%	Preserved LVEF >40%
Symptomatology	Identical—unable to differentiate with clinical examination	Identical—unable to differentiate with clinical examination
Long-term prognosis	15% annual mortality rate	5 to 8% annual mortality rate
MI, myocardial infarction; LVEF, left ventricular ejection fraction.

Diagnosis is made clinically

No consensus exists on standardized criteria for diagnosing diastolic heart failure. However, 3 diagnostic levels—possible, probable, and definite DHF—have been proposed by Vasan and Levy.¹¹

Possible DHF is defined as signs and symptoms of heart failure (TABLE 3) in patients with normal LV function, but lacking an assessment of ventricular function in proximity to the heart failure event.

Probable DHF is defined as (1) signs and symptoms of heart failure and (2) an ejection fraction >50% measured via echocardiography or radionuclide angio-graphy within 72 hours of the heart failure exacerbation.

Definite DHF is defined as (1) signs and symptoms of heart failure, (2) an ejection fraction >50% measured via the above methods within 72 hours of the patient’s presentation, and (3) increased left-ventricular end diastolic pressure (LVEDP) measured during cardiac catheterization.

TABLE 3
Modified Framingham criteria for diagnosing heart failure

Direct assessment of diastolic function unnecessary

Evidence of diastolic dysfunction as determined by echocardiography or cardiac catheterization has been debated as a necessary third diagnostic criterion.²⁴ The problem, though, is that there is no simple means of reliably diagnosing diastolic dysfunction with echocardiography (E:A ratios, deceleration or relaxation times), and that performing cardiac catheterization to measure LVEDP is impractical.²²

Furthermore, Zile et al have shown that, though cardiac catheterization helps to confirm diastolic dysfunction, it is not necessary to establish the diagnosis. In this study, 63 patients with clinically defined diastolic heart failure based on the Framingham criteria underwent diagnostic cardiac catheterization; 58 (92%) of these patients were also found to have an abnormal LVEDP, indicative of diastolic dysfunction.²⁵ Therefore, the diagnosis of DHF can be made in the setting of heart failure in a patient with a normal ejection fraction.

Order echocardiography within 72 hours of symptom onset

A major challenge for clinicians is to determine whether a patient’s dyspnea is a true symptom of heart failure. Signs and symptoms of heart failure must be defined using clinical indicators such as the Framingham heart failure criteria (FIGURE).²⁶ Diagnosis of heart failure is more easily made for a patient presenting to the emergency department with acute pulmonary edema than it is for an outpatient seen repeatedly for shortness of breath over months.

For a patient presenting with acute pulmonary edema, an echocardiogram should be performed within 72 hours of symptoms to document cardiac function in proximity to the heart failure exacerbation. The ejection fraction of patients with DHF can remain within normal range, even during acute decompensation.^27,28 Stroke volume and cardiac output may be decreased despite a normal ejection fraction.

Cardiogenic pulmonary edema in DHF patients results from the stiffened ventricle’s inability to compensate for increased venous return due to an expansion in central blood volume or sodium retention. Subsequently, diastolic pressures elevate and impede lung compliance, which increases the work of breathing and dyspnea.^20,29 A normal ejection fraction and symptom diminishment following diuresis in the setting of acute decompensation help confirm the diagnosis of DHF, especially when other disease states are complicating the clinical picture.³⁰

Elevated BNP levels may be helpful

An elevated level of b-type natriuretic peptide (BNP) can help confirm the clinical diagnosis of heart failure, and it has been shown in small studies to be a valid marker of DHF.^31,32 In a study of 294 patients referred for echocardiography to evaluate LV function, Lubien et al found that a BNP value of at least 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for heart failure in patients with a normal ejection fraction.³² All patients with systolic dysfunction defined by an ejection fraction <50% were excluded from this study. These results, though promising, must be confirmed by further studies evaluating the diagnostic utility of BNP to detect active heart failure symptoms in patients with diastolic dysfunction.

Treatment of symptomatic diastolic dysfunction

For SHF patients, multiple large outcome trials have clearly documented the benefit of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists in reducing mortality.^33-36 The relative paucity of outcome data for DHF has resulted in medical therapy primarily centered on modifying physiologic factors to improve LV filling and relaxation. Specifically, treatment should focus on symptom reduction, balancing fluid status, controlling heart rate, decreasing any ischemia, and achieving blood pressure goals.^19,20,22,31 Though many of the medications used to treat SHF are also used for DHF, there are several important differences in appropriate initiation and subsequent titration of these drugs in the 2 settings.^20,31

While treatment of DHF is largely theoretical, a limited number of well-designed, randomized studies are available to help determine appropriate therapy.^37-39TABLE 4 provides a summary of the evidence base for evaluation and treatment of systolic vs diastolic heart failure.⁴⁰TABLE 5 gives a synopsis of these studies. A suggested diagnostic and treatment approach for patients with DHF is outlined in the FIGURE. After determining whether a patient has DHF— primarily through the ruling out of other conditions and confirmation with echocardiographic studies—consider the applicability of each treatment based on a patient’s medical history and present condition.

TABLE 4
Comparative evidence base for evaluation and treatment of systolic vs diastolic heart failure

TABLE 5
Diastolic heart failure outcome trials